Central sympathoexcitatory actions of angiotensin II: role of type 1 angiotensin II receptors.

PubMed

DiBona, G F

1999-01-01

The role of the renin-angiotensin system in the control of sympathetic nerve activity is reviewed. Two general mechanisms are considered, one that involves the effects of circulating angiotensin II (AngII) on the central nervous system and a second that involves the central nervous system effects of AngII that originates within the central nervous system. The role of type 1 AngII receptors in discrete brain sites that mediate the sympathoexcitatory actions of AngII of either circulating or central nervous system origin is examined. AngII of circulating origin has ready access to the subfornical organ and area postrema, where it can bind to type 1 AngII receptors on neurons whose connections to the nucleus tractus solitarius and rostral ventrolateral medulla result in sympathoexcitation. In the rostral ventrolateral medulla, angiotensin peptides of central nervous system origin, likely involving angiotensin species in addition to AngII and binding to receptors other than type 1 or 2 AngII receptors, tonically support sympathetic nerve activity.

The effect of angiotensin-converting enzyme inhibition throughout a superovulation protocol in ewes.

PubMed

Pereira, Alécio Matos; de Souza Júnior, Antônio; Machado, Fernanda Brandão; Gonçalves, Gleisy Kelly Neves; Feitosa, Lauro César Soares; Reis, Adelina Martha; Santos, Robson Augusto Souza; Honorato-Sampaio, Kinulpe; Costa, Amilton Raposo

2015-12-01

Many studies identified new components of the renin–angiotensin system (RAS), such as Angiotensin-(1-7) [Ang-(1–7)] and Angiotensin-converting enzyme type 2 (ACE2), in mammalian ovaries.We previously showed Angiotensin-Converting Enzyme (ACE) inhibition, which increases the level of Ang-(1–7), stimulated ovarian estradiol output in ewe after estrous synchronization. Considering that Ang-(1–7) stimulates ovarian function and elevated estradiol before ovulation is associated with increased chance of achieving pregnancy, the present study investigated whether ACE inhibition throughout a superovulation protocol in ewe might improve ovulation outcome. At first, immunohistochemistry in ovaries of nonpregnant ewes revealed localization of Angiotensin II (Ang II), Ang-(1–7) and ACE2 in theca cells of antral follicles and in corpus luteum. Ang II and Ang-(1–7)were also detected in follicular fluid (FF) by Radioimmunoassay (RIA). Enalapril treatment throughout the superovulation protocol decreased 17β-estradiol (E2) output and raised progesterone:estradiol (P4:E2) ratio without a direct influence on ovulation and quality of embryos.

Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis.

PubMed

Ocaranza, Maria Paz; Moya, Jackeline; Barrientos, Victor; Alzamora, Rodrigo; Hevia, Daniel; Morales, Cristobal; Pinto, Melissa; Escudero, Nicolás; García, Lorena; Novoa, Ulises; Ayala, Pedro; Díaz-Araya, Guillermo; Godoy, Ivan; Chiong, Mario; Lavandero, Sergio; Jalil, Jorge E; Michea, Luis

2014-04-01

Little is known about the biological effects of angiotensin-(1-9), but available evidence shows that angiotensin-(1-9) has beneficial effects in preventing/ameliorating cardiovascular remodeling. In this study, we evaluated whether angiotensin-(1-9) decreases hypertension and reverses experimental cardiovascular damage in the rat. Angiotensin-(1-9) (600  ng/kg per min for 2 weeks) reduced already-established hypertension in rats with early high blood pressure induced by angiotensin II infusion or renal artery clipping. Angiotensin-(1-9) also improved cardiac (assessed by echocardiography) and endothelial function in small-diameter mesenteric arteries, cardiac and aortic wall hypertrophy, fibrosis, oxidative stress, collagen and transforming growth factor type β - 1 protein expression (assessed by western blot). The beneficial effect of angiotensin-(1-9) was blunted by coadministration of the angiotensin type 2(AT2) receptor blocker PD123319 (36  ng/kg per min) but not by coadministration of the Mas receptor blocker A779 (100  ng/kg per min). Angiotensin-(1-9) treatment also decreased circulating levels of Ang II, angiotensin-converting enzyme activity and oxidative stress in aorta and left ventricle. Whereas, Ang-(1-9) increased endothelial nitric oxide synthase mRNA levels in aorta as well as plasma nitrate levels. Angiotensin-(1-9) reduces hypertension, ameliorates structural alterations (hypertrophy and fibrosis), oxidative stress in the heart and aorta and improves cardiac and endothelial function in hypertensive rats. These effects were mediated by the AT2 receptor but not by the angiotensin-(1-7)/Mas receptor axis.

Calpain Inhibition Attenuates Angiotensin II-induced Abdominal Aortic Aneurysms and Atherosclerosis in LDL Receptor Deficient Mice

PubMed Central

Subramanian, Venkateswaran; Uchida, Haruhito Adam; Ijaz, Talha; Moorleghen, Jessica J.; Howatt, Deborah A.; Balakrishnan, Anju

2011-01-01

Chronic infusion of angiotensin II (AngII) augments atherosclerosis and abdominal aortic aneurysm (AAAs) formation in hypercholesterolemic mice. AngII-induced AAAs are associated with medial macrophage accumulation and matrix metalloproteinase (MMP) activation. Inhibition of calpain, a calcium-activated neutral cysteine protease, by overexpression of its endogenous inhibitor, calpastatin, attenuates AngII-induced leukocyte infiltration, perivascular inflammation, and MMP activation in mice. The purpose of this study was to define whether pharmacological inhibition of calpain influences AngII-induced AAAs in hypercholesterolemic mice. Male LDL receptor −/− mice were fed a fat-enriched diet and administered with either vehicle or a calpain-specific inhibitor, BDA-410 (30 mg/kg/day) for 5 weeks. After 1 week of feeding, mice were infused with AngII (1,000 ng/kg/min) for 4 weeks. AngII-infusion profoundly increased aortic calpain protein and activity. BDA-410 administration had no effect on plasma cholesterol concentrations or AngII-increased systolic blood pressure. Calpain inhibition significantly attenuated AngII-induced AAA formation and atherosclerosis development. BDA-410 administration attenuated activation of MMP12, pro-inflammatory cytokines (IL-6, MCP-1) and macrophage infiltration into the aorta. BDA-410 administration significantly attenuated thioglycollate-elicited macrophage accumulation in the peritoneal cavity. We conclude that calpain inhibition using BDA-410 attenuated AngII-induced AAA formation and atherosclerosis development in LDL receptor −/− mice. PMID:21964156

Evodiamine Inhibits Angiotensin II-Induced Rat Cardiomyocyte Hypertrophy.

PubMed

He, Na; Gong, Qi-Hai; Zhang, Feng; Zhang, Jing-Yi; Lin, Shu-Xian; Hou, Hua-Hua; Wu, Qin; Sun, An-Sheng

2018-05-01

To investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa (Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms. Cardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 μmol/L), and Evo (0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca 2+ ] i ) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis. Compared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca 2+ ] i ) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 μmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca 2+ ] i concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05). Evo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca 2+ ]i concentration, and inhibition of Ca

Control of adipogenesis by the autocrine interplays between angiotensin 1-7/Mas receptor and angiotensin II/AT1 receptor signaling pathways.

PubMed

Than, Aung; Leow, Melvin Khee-Shing; Chen, Peng

2013-05-31

Angiotensin II (AngII), a peptide hormone released by adipocytes, can be catabolized by adipose angiotensin-converting enzyme 2 (ACE2) to form Ang(1-7). Co-expression of AngII receptors (AT1 and AT2) and Ang(1-7) receptors (Mas) in adipocytes implies the autocrine regulation of the local angiotensin system upon adipocyte functions, through yet unknown interactive mechanisms. In the present study, we reveal the adipogenic effects of Ang(1-7) through activation of Mas receptor and its subtle interplays with the antiadipogenic AngII-AT1 signaling pathways. Specifically, in human and 3T3-L1 preadipocytes, Ang(1-7)-Mas signaling promotes adipogenesis via activation of PI3K/Akt and inhibition of MAPK kinase/ERK pathways, and Ang(1-7)-Mas antagonizes the antiadipogenic effect of AngII-AT1 by inhibiting the AngII-AT1-triggered MAPK kinase/ERK pathway. The autocrine regulation of the AngII/AT1-ACE2-Ang(1-7)/Mas axis upon adipogenesis has also been revealed. This study suggests the importance of the local regulation of the delicately balanced angiotensin system upon adipogenesis and its potential as a novel therapeutic target for obesity and related metabolic disorders.

Angiotensin-(1-7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Feng; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London; Ren, Jingyi

Highlights: Black-Right-Pointing-Pointer We for the first time found that Ang-(1-7) inhibits Ang II-induced VCAM-1 expression. Black-Right-Pointing-Pointer The inhibitory effect of Ang-(1-7) on VCAM-1 is mediated by MAS receptor. Black-Right-Pointing-Pointer The effect of Ang-(1-7) is due to the suppression of NF-kappaB translocation. -- Abstract: Angiotensin II (Ang II) and Angiotensin-(1-7) (Ang-(1-7)) are key effector peptides in the renin-angiotensin system. Increased circulatory Ang II level is associated with the development of hypertension and atherosclerosis, whereas Ang-(1-7) is a counter-regulatory mediator of Ang II which appears to be protective against cardiovascular disease. However, whether Ang-(1-7) regulates the action of Ang II on vascularmore » endothelial cells (EC) remains unclear. We investigated the effects of Ang II and Ang-(1-7) in the context of atherogenesis, specifically endothelial cell VCAM-1 expression that is implicated in early plaque formation. The results show that Ang II increased VCAM-1 mRNA expression and protein displayed on EC surface, while Ang-(1-7) alone exerted no effects. However, Ang-(1-7) significantly suppressed Ang II-induced VCAM-1 expression. Ang-(1-7) also inhibited the Ang II-induced VCAM-1 promoter activity driven by transcription factor NF-KappaB. Furthermore, immunofluorescence assay and ELISA showed that Ang II facilitated the nuclear translocation of NF-kappaB in ECs, and this was attenuated by the presence of Ang-(1-7). The inhibitory effects of Ang-(1-7) on Ang II-induced VCAM-1 promoter activity and NF-kappaB nuclear translocation were all reversed by the competitive antagonist of Ang-(1-7) at the Mas receptor. Our results suggest that Ang-(1-7) mediates its affects on ECs through the Mas receptor, and negatively regulates Ang II-induced VCAM-1 expression by attenuating nuclear translocation of NF-kappaB.« less

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

PubMed Central

Giani, Jorge F.; Janjulia, Tea; Kamat, Nikhil; Seth, Dale M.; Blackwell, Wendell-Lamar B.; Shah, Kandarp H.; Shen, Xiao Z.; Fuchs, Sebastien; Delpire, Eric; Toblli, Jorge E.; Bernstein, Kenneth E.; McDonough, Alicia A.

2014-01-01

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na+/H+ exchanger 3, Na+/Pi co-transporter 2, phosphorylated Na+/K+/Cl− cotransporter, and phosphorylated Na+/Cl− cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na+ channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition. PMID:25012170

DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

PubMed Central

Jurado-López, Raquel; Martínez-Martínez, Ernesto; Gómez-Hurtado, Nieves; Delgado, Carmen; Visitación Bartolomé, Maria; San Román, José Alberto; Cordova, Claudia; Lahera, Vicente; Nieto, Maria Luisa; Cachofeiro, Victoria

2012-01-01

myofibroblasts. They inhibit the angiotensin II-induced proliferation in a PPAR-γ-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-γ. PMID:22844495

Vaccination: a novel strategy for inhibiting the renin-angiotensin-aldosterone system.

PubMed

Gradman, Alan H; Pinto, Rehka

2008-12-01

Immunologic approaches to renin-angiotensin-aldosterone system (RAAS) inhibition have been studied for more than 50 years. In animal models, vaccination against renin was effective but resulted in fatal autoimmune renal disease; vaccines directed at small peptides including angiotensin I and II and a segment of the AT(1) receptor reduced blood pressure (BP) without causing autoimmune disease. In humans, angiotensin I vaccination did not reduce BP. More promising is the AngQb vaccine, which uses an immunization technology involving conjugation of angiotensin II to virus-like particles. In a phase 2 trial, hypertensive patients vaccinated with 300 microg showed a difference of 9.0/4.0 mm Hg from baseline in mean daytime ambulatory BP after 14 weeks (P = 0.015 for systolic BP, P = 0.064 for diastolic BP), and a marked reduction in early morning BP. No serious adverse events were attributed to vaccine administration. Although questions remain regarding efficacy and safety, RAAS immunization represents an innovative and promising approach to hypertension treatment.

Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats

PubMed Central

Chen, Jin-Shuen

2017-01-01

Renin–angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar–Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. PMID:28700686

Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats.

PubMed

Chou, Chu-Lin; Lin, Heng; Chen, Jin-Shuen; Fang, Te-Chao

2017-01-01

Renin-angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Angiotensin-(1-7) augments endothelium-dependent relaxations of porcine coronary arteries to bradykinin by inhibiting angiotensin-converting enzyme 1.

PubMed

Raffai, Gábor; Khang, Gilson; Vanhoutte, Paul M

2014-05-01

Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II to angiotensin-(1-7) that activates Mas receptors, inhibits ACE1, and modulates bradykinin receptor sensitivity. This in vitro study compared the direct and indirect effects of angiotensin-(1-7), the ACE1 inhibitor captopril, and diminazene aceturate (DIZE) an alleged ACE2 activator in rings of porcine coronary arteries, by measuring changes of isometric tension. Angiotensin-(1-7), captopril, and DIZE did not cause significant changes in tension before or after desensitization of bradykinin receptors in preparations contracted with U46619. Bradykinin caused concentration-dependent and endothelium-dependent relaxations that were not affected by DIZE but were potentiated to a similar extent by angiotensin-(1-7) and captopril, given alone or in combination. Bradykinin responses potentiated by angiotensin-(1-7) and captopril were not affected by the BK1 antagonist SSR240612 and remained augmented in the presence of either N-nitro-L-arginine methyl ester hydrochloride plus indomethacin or TRAM-34 plus UCL-1684. ACE2 was identified in the coronary endothelium by immunofluorescence, but its basal activity was not influenced by DIZE. These results suggest that in coronary arteries, angiotensin-(1-7) and captopril both improves NO bioavailability and enhances endothelium-dependent hyperpolarization to bradykinin solely by ACE1 inhibition. Endothelial ACE2 activity cannot be increased by DIZE to produce local adequate amounts of angiotensin-(1-7) to influence vascular tone.

Angiotensin II induces water absorption behavior in two species of desert anurans.

PubMed

Propper, C R; Johnson, W E

1994-03-01

The octapeptide, angiotensin II (A-II), induces drinking behavior in several vertebrate species; however, relatively little is understood about A-II-induced thirst in amphibians. Scaphiopus couchii and Bufo cognatus were dehydrated to 90% of their ad libitum weight. This level of dehydration was sufficient to induce water absorption response (WR) behavior in both species. Fully hydrated toads injected intraperitoneally with A-II exhibited a significant amount of WR behavior. The minimum effective dose for inducing WR behavior was 10 micrograms/100 g-animal for S. couchii and 100 micrograms/100 g-animal for B. cognatus. When dehydrated toads were treated with the A-II receptor antagonist, Thr8-saralasin, S. couchii, exhibited a significant increase in WR behavior, while B. cognatus did not respond behaviorally. Finally, treatment of dehydrated toads with captopril, a compound that inhibits conversion of angiotensin I to A-II, did not significantly affect WR behavior in either species. These results support other findings that A-II may be involved in WR behavior in amphibians. However, the failure of Thr2-saralasin or captopril to inhibit WR behavior in dehydrated toads suggests that the receptor mechanisms involved in thirst regulation in toads may be different from those in mammals, and the renin-angiotensin system may not be the only potential mediator of WR behavior in these species.

Effect of angiotensin II on proliferation and differentiation of mouse induced pluripotent stem cells into mesodermal progenitor cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishizuka, Toshiaki, E-mail: tishizu@ndmc.ac.jp; Goshima, Hazuki; Ozawa, Ayako

2012-03-30

Highlights: Black-Right-Pointing-Pointer Treatment with angiotensin II enhanced LIF-induced DNA synthesis of mouse iPS cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the DNA synthesis via induction of superoxide. Black-Right-Pointing-Pointer Treatment with angiotensin II significantly increased JAK/STAT3 phosphorylation. Black-Right-Pointing-Pointer Angiotensin II enhanced differentiation into mesodermal progenitor cells. Black-Right-Pointing-Pointer Angiotensin II may enhance the differentiation via activation of p38 MAPK. -- Abstract: Previous studies suggest that angiotensin receptor stimulation may enhance not only proliferation but also differentiation of undifferentiated stem/progenitor cells. Therefore, in the present study, we determined the involvement of the angiotensin receptor in the proliferation and differentiation of mouse induced pluripotent stemmore » (iPS) cells. Stimulation with angiotensin II (Ang II) significantly increased DNA synthesis in mouse iPS cells cultured in a medium with leukemia inhibitory factor (LIF). Pretreatment of the cells with either candesartan (a selective Ang II type 1 receptor [AT{sub 1}R] antagonist) or Tempol (a cell-permeable superoxide scavenger) significantly inhibited Ang II-induced DNA synthesis. Treatment with Ang II significantly increased JAK/STAT3 phosphorylation. Pretreatment with candesartan significantly inhibited Ang II- induced JAK/STAT3 phosphorylation. In contrast, induction of mouse iPS cell differentiation into Flk-1-positive mesodermal progenitor cells was performed in type IV collagen (Col IV)- coated dishes in a differentiation medium without LIF. When Col IV-exposed iPS cells were treated with Ang II for 5 days, the expression of Flk-1 was significantly increased compared with that in the cells treated with the vehicle alone. Pretreatment of the cells with both candesartan and SB203580 (a p38 MAPK inhibitor) significantly inhibited the Ang II- induced increase in Flk-1 expression

Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro)renin receptor and intrarenal renin-angiotensin system.

PubMed

Wang, Lei; Zhu, Qing; Lu, Aihua; Liu, Xiaofen; Zhang, Linlin; Xu, Chuanming; Liu, Xiyang; Li, Haobo; Yang, Tianxin

2017-09-01

Butyrate, a short-chain fatty acid, is the end product of the fermentation of complex carbohydrates by the gut microbiota. Recently, sodium butyrate (NaBu) has been found to play a protective role in a number of chronic diseases. However, it is still unclear whether NaBu has a therapeutic potential in hypertension. The present study was aimed to investigate the role of NaBu in angiotensin II (Ang II)-induced hypertension and to further explore the underlying mechanism. Ang II was infused into uninephrectomized Sprague-Dawley rats with or without intramedullary infusion of NaBu for 14 days. Mean arterial blood pressure was recorded by the telemetry system. Renal tissues, serum samples, and 24-h urine samples were collected to examine renal injury and the regulation of the (pro)renin receptor (PRR) and renin. Intramedullary infusion of NaBu in Sprague-Dawley rats lowered the Ang II-induced mean arterial pressure from 129 ± 6 mmHg to 108 ± 4 mmHg (P < 0.01). This corresponded with an improvement in Ang II-induced renal injury, including urinary albumin, glomerulosclerosis, and renal fibrosis, as well as the expression of inflammatory mediators tumor necrosis factor α, interleukin 6. The renal expression of PRR, angiotensinogen, angiotensin I-converting enzyme and the urinary excretion of soluble PRR, renin, and angiotensinogen were all increased by Ang II infusion but decreased by NaBu treatment. In cultured innermedullary collecting duct cells, NaBu treatment attenuated Ang II-induced expression of PRR and renin. These results demonstrate that NaBu exerts an antihypertensive action, likely by suppressing the PRR-mediated intrarenal renin-angiotensin system.

Documentation of angiotensin II receptors in glomerular epithelial cells

NASA Technical Reports Server (NTRS)

Sharma, M.; Sharma, R.; Greene, A. S.; McCarthy, E. T.; Savin, V. J.; Cowley, A. W. (Principal Investigator)

1998-01-01

Angiotensin II decreases glomerular filtration rate, renal plasma flow, and glomerular capillary hydraulic conductivity. Although angiotensin II receptors have been demonstrated in mesangial cells and proximal tubule cells, the presence of angiotensin II receptors in glomerular epithelial cells has not previously been shown. Previously, we have reported that angiotensin II caused an accumulation of cAMP and a reorganization of the actin cytoskeleton in cultured glomerular epithelial cells. Current studies were conducted to verify the presence of angiotensin II receptors by immunological and non-peptide receptor ligand binding techniques and to ascertain the activation of intracellular signal transduction in glomerular epithelial cells in response to angiotensin II. Confluent monolayer cultures of glomerular epithelial cells were incubated with angiotensin II, with or without losartan and/or PD-123,319 in the medium. Membrane vesicle preparations were obtained by homogenization of washed cells followed by centrifugation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membrane proteins followed by multiscreen immunoblotting was used to determine the presence of angiotensin II receptor type 1 (AT1) or type 2 (AT2). Angiotensin II-mediated signal transduction in glomerular epithelial cells was studied by measuring the levels of cAMP, using radioimmunoassay. Results obtained in these experiments showed the presence of both AT1 and AT2 receptor types in glomerular epithelial cells. Angiotensin II was found to cause an accumulation of cAMP in glomerular epithelial cells, which could be prevented only by simultaneous use of losartan and PD-123,319, antagonists for AT1 and AT2, respectively. The presence of both AT1 and AT2 receptors and an increase in cAMP indicate that glomerular epithelial cells respond to angiotensin II in a manner distinct from that of mesangial cells or proximal tubular epithelial cells. Our results suggest that glomerular epithelial

Angiotensin-converting enzyme inhibition studies by natural leech inhibitors by capillary electrophoresis and competition assay.

PubMed

Deloffre, Laurence; Sautiere, Pierre-Eric; Huybrechts, Roger; Hens, Korneel; Vieau, Didier; Salzet, Michel

2004-06-01

A protocol to follow the processing of angiotensin I into angiotensin II by rabbit angiotensin-converting enzyme (ACE) and its inhibition by a novel natural antagonist, the leech osmoregulator factor (LORF) using capillary zonal electrophoresis is described. The experiment was carried out using the Beckman PACE system and steps were taken to determine (a) the migration profiles of angiotensin and its yielded peptides, (b) the minimal amount of angiotensin II detected, (c) the use of different electrolytes and (d) the concentration of inhibitor. We demonstrated that LORF (IPEPYVWD), a neuropeptide previously found in leech brain, is able to inhibit rabbit ACE with an IC(50) of 19.8 micro m. Interestingly, its cleavage product, IPEP exhibits an IC(50) of 11.5 micro m. A competition assay using p-benzoylglycylglycylglycine and insect ACE established that LORF and IPEP fragments are natural inhibitors for invertebrate ACE. Fifty-four percent of insect ACE activity is inhibited with 50 micro m IPEP and 35% inhibition with LORF (25 mm). Extending the peptide at both N- and C-terminus (GWEIPEPYVWDES) and the cleavage of IPEP in IP abolished the inhibitory activity of both peptides. Immunocytochemical data obtained with antisera raised against LORF and leech ACE showed a colocalization between the enzyme and its inhibitor in the same neurons. These results showed that capillary zonal electrophoresis is a useful technique for following enzymatic processes with small amounts of products and constitutes the first evidence of a natural ACE inhibitor in invertebrates.

sRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting RAGE-NFκB-NLRP3 activation.

PubMed

Lim, Soyeon; Lee, Myung Eun; Jeong, Jisu; Lee, Jiye; Cho, Soyoung; Seo, Miran; Park, Sungha

2018-05-23

The receptor for advanced glycation endproducts (RAGE) is an innate immunity receptor that has been implicated in the pathogenesis of atherosclerotic cardiovascular disease. However, the possibility that RAGE-mediated signaling is involved in angiotensin II (Ang II)-induced cardiac left ventricular hypertrophy has yet to be investigated. We therefore determined whether RAGE has a role in regulating pathological cardiac hypertrophy. Protein abundance was estimated using Western blotting and intracellular ROS level and phospho-p65 were detected using fluorescence microscopy. Enzyme-linked immunosorbent assay was used to detect HMGB1 and IL-1β. All in vitro experiments were performed using H9C2 cells. To induce cardiomyocyte hypertrophy, 300 nM Ang II was treated for 48 h and 2 µg/ml sRAGE was treated 1 h prior to addition of Ang II. sRAGE attenuated Ang II-induced cardiomyocyte hypertrophy by downregulating RAGE and angiotensin II type 1 receptor expression. Secretion levels of high motility group box 1 and interleukin-1β, estimated from a cell culture medium, were significantly reduced by sRAGE. Activated PKCs and ERK1/2, important signals in left ventricular hypertrophy (LVH) development, were downregulated by sRAGE treatment. Furthermore, we found that nuclear factor-κB and NOD-like receptor protein 3 (NLRP3) were associated with RAGE-mediated cardiomyocyte hypertrophy. In the context of these results, we conclude that RAGE induces cardiac hypertrophy through the activation of the PKCs-ERK1/2 and NF-κB-NLRP3-IL1β signaling pathway, and suggest that RAGE-NLRP3 may be an important mediator of Ang II-induced cardiomyocyte hypertrophy. In addition, we determined that inhibition of RAGE activation with soluble RAGE (sRAGE) has a protective effect on Ang II-induced cardiomyocyte hypertrophy.

Effect of endogenous angiotensin II on the frequency response of the renal vasculature.

PubMed

Dibona, Gerald F; Sawin, Linda L

2004-12-01

The renal vasculature functions as an efficient low-pass filter of the multiple frequencies contained within renal sympathetic nerve activity. This study examined the effect of angiotensin II on the frequency response of the renal vasculature. Physiological changes in the activity of the endogenous renin-angiotensin system were produced by alterations in dietary sodium intake. The frequency response of the renal vasculature was evaluated using pseudorandom binary sequence renal nerve stimulation, and the role of angiotensin II was evaluated by the administration of the angiotensin II AT(1)-receptor antagonist losartan. In low-sodium-diet rats with increased renin-angiotensin system activity, losartan steepened the renal vascular frequency response (i.e., greater attenuation); this was not seen in normal- or high-sodium-diet rats with normal or decreased renin-angiotensin system activity. Analysis of the transfer function from arterial pressure to renal blood flow, i.e., dynamic autoregulation, showed that the tubuloglomerular feedback but not the myogenic component was enhanced in low- and normal- but not in high-sodium-diet rats and that this was reversed by losartan administration. Thus physiological increases in endogenous renin-angiotensin activity inhibit the renal vascular frequency response to renal nerve stimulation while selectively enhancing the tubuloglomerular feedback component of dynamic autoregulation of renal blood flow.

Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata.

PubMed

Allen, A M; Chai, S Y; Clevers, J; McKinley, M J; Paxinos, G; Mendelsohn, F A

1988-03-08

Angiotensin II receptor and angiotensin converting enzyme distributions in the human medulla oblongata were localised by quantitative in vitro autoradiography. Angiotensin II receptors were labelled with the antagonist analogue 125I-[Sar1, Ile8] AII while angiotensin converting enzyme was labelled with 125I-351A, a derivative of the specific converting enzyme inhibitor, lisinopril. Angiotensin II receptor binding and angiotensin converting enzyme are present in high concentrations in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral reticular nucleus, and in a band connecting the dorsal and ventral regions. In the rostral and caudal ventrolateral reticular nucleus, angiotensin II receptors are distributed in a punctate pattern that registers with neuronal cell bodies. The distribution and density of these cell bodies closely resemble those of catecholamine-containing neurones mapped by others. In view of the known interactions of angiotensin II with both central and peripheral catecholamine-containing neurons of laboratory animals, the current anatomical findings suggest similar interactions between these neuroactive compounds in the human central nervous system. The presence of angiotensin II receptors and angiotensin converting enzyme in the nucleus of the solitary tract, dorsal motor nucleus of vagus, and rostral and caudal ventrolateral reticular nucleus demonstrates sites for central angiotensin II to exert its known actions on vasopressin release and autonomic functions including blood pressure control. These data also suggest a possible interaction between angiotensin II and central catecholeminergic systems.

Tumor necrosis factor-α inhibits angiotensin II receptor type 1 expression in dorsal root ganglion neurons via β-catenin signaling.

PubMed

Yang, Y; Wu, H; Yan, J-Q; Song, Z-B; Guo, Q-L

2013-09-17

Both tumor necrosis factor (TNF)-α and the angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) axis play important roles in neuropathic pain and nociception. In the present study, we explored the interaction between the two systems by examining the mutual effects between TNF-α and the Ang II/AT1 receptor axis in dorsal root ganglion (DRG) neurons. Rat DRG neurons were treated with TNF-α in different concentrations for different lengths of time in the presence or absence of transcription inhibitor actinomycin D, TNF receptor 1 (TNFR1) inhibitor SPD304, β-catenin signaling inhibitor CCT031374, or different kinase inhibitors. TNF-α decreased the AT1 receptor mRNA level as well as the AT1a receptor promoter activity in a dose-dependent manner within 30 h, which led to dose-dependent inhibition of Ang II-binding AT1 receptor level on the cell membrane. Actinomycin D (1 mg/ml), SPD304 (50 μM), p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 (25 μM), and CCT031374 (50 μM) completely abolished the inhibitory effect of TNF-α on AT1 receptor expression. TNF-α dose-dependently increased soluble β-catenin and phosphorylated GSK-3β levels, which was blocked by SPD304 and PD169316. In DRG neurons treated with AT2 receptor agonist CGP421140, or Ang II with or without AT1 receptor antagonist losartan or AT2 receptor antagonist PD123319 for 30 h, we found that Ang II and Ang II+PD123319 significantly decreased TNF-α expression, whereas CPG421140 and Ang II+losartan increased TNF-α expression. In conclusion, we demonstrate that TNF-α inhibits AT1 receptor expression at the transcription level via TNFR1 in rat DRG neurons by increasing the soluble β-catenin level through the p38 MAPK/GSK-3β pathway. In addition, Ang II appears to inhibit and induce TNF-α expression via the AT1 receptor and the AT2 receptor in DRG neurons, respectively. This is the first evidence of crosstalk between TNF-α and the Ang II/AT receptor axis in DRG neurons

The granulocyte-angiotensin system. Angiotensin I-converting activity of cathepsin G.

PubMed

Klickstein, L B; Kaempfer, C E; Wintroub, B U

1982-12-25

Cathepsin G, an Mr = 26,000-29,000 cationic human neutrophil lysosomal serine protease, releases angiotensin II from angiotensinogen and was, therefore, examined for angiotensin I-converting activity. Cathepsin G-dependent angiotensin I conversion was detected by a high performance liquid chromatography assay which permitted independent quantitation of angiotensin I and angiotensin II and detection of angiotensin degradation products. 1.8-5.0 X 10(-9) M cathepsin G converted angiotensin I (3.3 X 10(-4) M) to angiotensin II without further degradation of angiotensin II. The pH optimum for cathepsin G-catalyzed angiotensin I conversion was pH 7.0-7.5, and the Km and Kcat were 2.2 X 10(-4) M and 3.4 s-1, respectively. In contrast to dipeptidyl hydrolase-converting enzyme, cathepsin G did not inactivate bradykinin, did not cleave hippuryl-His-Leu, and was not inhibited by 10(-4) M Captopril or SQ 20881. Purified human neutrophils stimulated with 2.5 X 10(-6) M-10(-10) M fMet-Leu-Phe released angiotensin-converting activity with a Km of 3.3 X 10(-4) M. That the angiotensin-converting activity released from neutrophils was attributable to cathepsin G was indicated by similar susceptibility to inhibitors and adsorption by goat antibody to cathepsin G. The granulocyte-angiotensin system provides a mechanism for the local generation of angiotensin II at sites of neutrophil accumulation and may be of significance in regulation of blood flow in tissue microvasculature.

Mineral Metabolites, Angiotensin II Inhibition and Outcomes in Advanced Chronic Kidney Disease.

PubMed

Jovanovich, Anna J; Chonchol, Michel B; Sobhi, Atousa; Kendrick, Jessica B; Cheung, Alfred K; Kaufman, James S; Smits, Gerard; Jablonski, Kristen L

2015-01-01

Evidence suggests that the renin-angiotensin-aldosterone system (RAAS) interacts with the vitamin D-fibroblast growth factor 23-Klotho axis. We investigated whether circulating mineral metabolism markers modify outcomes in response to RAAS inhibition in subjects with advanced chronic kidney disease (CKD). In this retrospective cohort study, we analyzed the association of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use with all-cause mortality and dialysis initiation among 1,753 subjects (1,099 CKD, estimated glomerular filtration rate 18 ± 6 ml/min/1.73 m(2) and 654 end-stage renal disease [ESRD]) from the Homocysteine in Kidney and End Stage Renal Disease (HOST) study. A propensity score analysis accounted for indication bias and Cox regression models adjusted for mineral metabolism markers. Mean follow-up was 3.2 years; 714 (41%) subjects died and 615 (56%) initiated dialysis. In adjusted analyses, all subjects treated with ACEI/ARB had a significantly lower hazard of death (hazards ratio (HR) 0.81, 95% CI 0.70-0.95, p = 0.007). Those with CKD not on dialysis and treated with ACEI/ARB trended toward a lower hazard of dialysis initiation (HR 0.86, 95% CI 0.73-1.01, p = 0.06). The association with mortality did not differ by level of mineral metabolism marker (p for interaction >0.16); however, the relationship with dialysis initiation differed according to the median serum phosphorus level (p for interaction <0.001). RAAS inhibition was associated with decreased all-cause mortality independent of disordered mineral metabolism among mostly male HOST subjects with advanced CKD and ESRD. However, among those with CKD not requiring dialysis, the renoprotection associated with RAAS inhibition was attenuated by higher serum phosphorus levels. Further studies are needed to confirm this association. © 2015 S. Karger AG, Basel.

Inhibitory effects of losartan and azelnidipine on augmentation of blood pressure variability induced by angiotensin II in rats.

PubMed

Jiang, Danfeng; Kawagoe, Yukiko; Kuwasako, Kenji; Kitamura, Kazuo; Kato, Johji

2017-07-05

Increased blood pressure variability has been shown to be associated with cardiovascular morbidity and mortality. Recently we reported that continuous infusion of angiotensin II not only elevated blood pressure level, but also increased blood pressure variability in a manner assumed to be independent of blood pressure elevation in rats. In the present study, the effects of the angiotensin type I receptor blocker losartan and the calcium channel blocker azelnidipine on angiotensin II-induced blood pressure variability were examined and compared with that of the vasodilator hydralazine in rats. Nine-week-old male Wistar rats were subcutaneously infused with 240 pmol/kg/min angiotensin II for two weeks without or with oral administration of losartan, azelnidipine, or hydralazine. Blood pressure variability was evaluated using a coefficient of variation of blood pressure recorded every 15min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. Treatment with losartan suppressed both blood pressure elevation and augmentation of systolic blood pressure variability in rats infused with angiotensin II at 7 and 14 days. Azelnidipine also inhibited angiotensin II-induced blood pressure elevation and augmentation of blood pressure variability; meanwhile, hydralazine attenuated the pressor effect of angiotensin II, but had no effect on blood pressure variability. In conclusion, angiotensin II augmented blood pressure variability in an angiotensin type 1 receptor-dependent manner, and azelnidipine suppressed angiotensin II-induced augmentation of blood pressure variability, an effect mediated by the mechanism independent of the blood pressure-lowering action. Copyright © 2017 Elsevier B.V. All rights reserved.

Activation of PPARδ counteracts angiotensin II-induced ROS generation by inhibiting rac1 translocation in vascular smooth muscle cells.

PubMed

Lee, Hanna; Ham, Sun Ah; Kim, Min Young; Kim, Jae-Hwan; Paek, Kyung Shin; Kang, Eun Sil; Kim, Hyo Jung; Hwang, Jung Seok; Yoo, Taesik; Park, Chankyu; Kim, Jin-Hoi; Lim, Dae-Seog; Han, Chang Woo; Seo, Han Geuk

2012-07-01

Angiotensin II (Ang II)-mediated modification of the redox milieu of vascular smooth muscle cells (VSMCs) has been implicated in several pathophysiological processes, including cell proliferation, migration and differentiation. In this study, we demonstrate that the peroxisome proliferator-activated receptor (PPAR) δ counteracts Ang II-induced production of reactive oxygen species (ROS) in VSMCs. Activation of PPARδ by GW501516, a specific ligand for PPARδ, significantly reduced Ang II-induced ROS generation in VSMCs. This effect was, however, reversed in the presence of small interfering (si)RNA against PPARδ. The marked increase in ROS levels induced by Ang II was also eliminated by the inhibition of phosphatidylinositol 3-kinase (PI3K) but not of protein kinase C, suggesting the involvement of the PI3K/Akt signalling pathway in this process. Accordingly, ablation of Akt with siRNA further enhanced the inhibitory effects of GW501516 in Ang II-induced superoxide production. Ligand-activated PPARδ also blocked Ang II-induced translocation of Rac1 to the cell membrane, inhibiting the activation of NADPH oxidases and consequently ROS generation. These results indicate that ligand-activated PPARδ plays an important role in the cellular response to oxidative stress by decreasing ROS generated by Ang II in vascular cells.

Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia.

PubMed

Stanhewicz, Anna E; Jandu, Sandeep; Santhanam, Lakshmi; Alexander, Lacy M

2017-08-01

Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10 -7 -102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME ( N G -nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10 -20 -10 -4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 log EC50 ; P <0.001) and NO-dependent dilation (16±3% versus 39±6%; P =0.006). Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; P =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had

Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney.

PubMed

Talati, Gulibaha; Ohta, Akihito; Rai, Tatemitsu; Sohara, Eisei; Naito, Shotaro; Vandewalle, Alain; Sasaki, Sei; Uchida, Shinichi

2010-03-19

In our recent study using Wnk4(D561A/+) knockin mice, we determined that the WNK-OSR1/SPAK-NaCl cotransporter (NCC) phosphorylation cascade is important for regulating NCC function in vivo. Phosphorylation of NCC was necessary for its plasma membrane localization. Previously, angiotensin II infusion was shown to increase apical membrane expression of NCC in rats. Therefore, we investigated whether angiotensin II was an upstream regulator for the WNK-OSR1/SPAK-NCC cascade in cultured cells and in vivo kidney. In mpkDCT cells, the phosphorylation of OSR1 and NCC was increased 30 min after the addition of angiotensin II (10(-9)-10(-7)M) but returned to baseline after 18 h. In mice, a 5-min infusion of angiotensin II (5 ng/g/min) increased NCC phosphorylation in the kidney at 30 min and 2h after the injection but returned to baseline 24h later. This increase was inhibited by angiotensin II receptor blocker (valsartan) but not by aldosterone receptor blocker (eplerenone). Ten-day infusions of angiotensin II (720 ng/day) also increased phosphorylation of OSR1 and NCC in the mouse kidney, and both valsartan and eplerenone inhibited the increased phosphorylation. Although angiotensin II is identified as an upstream regulator for the WNK-OSR1/SPAK-NCC cascade in vivo, aldosterone appears to be the major regulator of this signal cascade in the long-term regulation by angiotensin II. Copyright 2010 Elsevier Inc. All rights reserved.

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Qing; Qin, Da-Nian, E-mail: dnqin@stu.edu.cn; Wang, Fu-Xin

Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympatheticmore » nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.« less

Angiotensin II Receptor Blockers

MedlinePlus

... 2010. Mann JFE, et al. Renin-angiotensin system inhibition in the treatment of hypertension. http://www.uptodate. ... profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any ...

Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease.

PubMed

Wiesmann, Maximilian; Roelofs, Monica; van der Lugt, Robert; Heerschap, Arend; Kiliaan, Amanda J; Claassen, Jurgen Ahr

2017-07-01

Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced hypertension on systolic blood pressure, and treatment with the angiotensin II receptor blockers, eprosartan mesylate, after one month of induced hypertension in wild-type C57bl/6j and AβPPswe/PS1ΔE9 (AβPP/PS1/Alzheimer's disease) mice. AβPP/PS1 showed higher systolic blood pressure than wild-type. Subsequent eprosartan mesylate treatment restored this elevated systolic blood pressure in all mice. Functional connectivity was decreased in angiotensin II-infused Alzheimer's disease and wild-type mice, and only 12 months of Alzheimer's disease mice showed impaired cerebral blood flow. Only angiotensin II-infused Alzheimer's disease mice exhibited decreased spatial learning in the Morris water maze. Altogether, angiotensin II-induced hypertension not only exacerbated Alzheimer's disease-like pathological changes such as impairment of cerebral blood flow, functional connectivity, and cognition only in Alzheimer's disease model mice, but it also induced decreased functional connectivity in wild-type mice. However, we could not detect hypertension-induced overexpression of Aβ nor increased neuroinflammation. Our findings suggest a link between midlife hypertension, decreased cerebral hemodynamics and connectivity in an Alzheimer's disease mouse model. Eprosartan mesylate treatment restored and beneficially affected cerebral blood flow and connectivity. This model could be used to investigate prevention/treatment strategies in early Alzheimer's disease.

The role of angiotensin II in the renal responses to somatic nerve stimulation in the rat.

PubMed Central

Handa, R K; Johns, E J

1987-01-01

1. Electrical stimulation of the brachial nerves at 3 Hz (15 V, 0.2 ms), in sodium pentobarbitone-anaesthetized rats whose renal arterial pressure was held constant, elicited a 26% increase in systemic blood pressure, a 15% rise in heart rate, an 11% reduction in renal blood flow, did not alter glomerular filtration rate and significantly reduced absolute and fractional sodium excretions and urine flow by 44, 49 and 31%, respectively. 2. In a separate group of rats, brachial nerve stimulation at 3 Hz increased plasma renin activity approximately 2-fold, while in animals in which the brachial nerves were not stimulated plasma renin activity did not change. 3. Following inhibition of the renin-angiotensin system with captopril or sar-1-ile-8-angiotensin II, brachial nerve stimulation resulted in similar increases in systemic blood pressure and heart rate as in the animals with an intact renin-angiotensin system but, in captopril-infused rats, did not change renal haemodynamics or urine flow while absolute and fractional sodium excretions were reduced by 20 and 25%, respectively. In sar-1-ile-8-angiotensin II-infused animals, similar nerve stimulation decreased renal blood flow by 12%, glomerular filtration rate by 7% and absolute and fractional sodium excretions and urine flow by 25, 18 and 18%, respectively. These decreases in sodium and water output were significantly smaller than those observed in animals with an intact renin-angiotensin system. 4. Stimulation of the brachial nerves increased post-ganglionic efferent renal nerve activity by 20% and the magnitude of this response was unaffected following inhibition of the renin-angiotensin system. 5. The results show that low rates of brachial nerve stimulation in the rat can increase efferent renal nerve activity and result in an antinatriuresis and antidiuresis which is dependent on the presence of angiotensin II, and appears to be due to an action of angiotensin II at the level of the kidney. PMID:3328780

Albuminuria in mice after injection of antibodies against aminopeptidase A: role of angiotensin II.

PubMed

Gerlofs-Nijland, M E; Assmann, K J; Dijkman, H B; Dieker, J W; van Son, J P; Mentzel, S; van Kats, J P; Danser, A H; Smithies, O; Groenen, P J; Wetzels, J F

2001-12-01

It has been shown that injection of combinations of anti-aminopeptidase A (APA) monoclonal antibodies (mAb) that inhibit the enzyme activity induces an acute albuminuria in mice. This albuminuria is not dependent on inflammatory cells, complement, or the coagulation system. APA is an important regulator of the renin-angiotensin system because it is involved in the degradation of angiotensin II (Ang II). This study examined the potential role of glomerular Ang II in the induction of albuminuria. The relation among renal Ang II, glomerular APAX enzyme activity, and albuminuria was examined first. Injection of the nephritogenic combinations ASD-3/37 and ASD-37/41 in BALB/c mice induced albuminuria, whereas the non-nephritogenic combination ASD-3/41 had no effect. There was no clear relation between the inhibition of glomerular APA activity and albuminuria, yet it was evident that intrarenal Ang II levels were significantly increased in albuminuric mice and not in nonalbuminuric mice. As a next step, anti-APA mAb were administered to angiotensinogen-deficient mice that do not produce Ang II, and kidney morphology and albuminuria were determined. Angiotensinogen-deficient mice also developed albuminuria upon ASD-37/41 administration. Altogether, these findings clearly demonstrate that Ang II is not required for the induction of albuminuria upon injection of enzyme-inhibiting anti-APA mAb.

Angiotensin converting enzyme inhibition and the kidney

NASA Technical Reports Server (NTRS)

Hollenberg, N. K.

1988-01-01

Angiotensin II (Ang II) induces a marked reduction in renal blood flow at doses well below those required to induce a pressor response, and as blood flow falls there is a decline in glomerular filtration rate and sodium excretion. This striking sensitivity of the renal blood supply led many workers to consider the possibility that angiotensin functions as a local renal hormone. As angiotensin converting enzyme (ACE) was found in particular abundance in the lung, it seemed reasonable to suspect that most of the conversion occurred there, and that the function of Ang II would be primarily systemic, rather than intrarenal. In this review, I will explore the evidence that has accumulated on these two possibilities, since they have important implications for our current understanding of normal kidney function and derangements of kidney function in disease.

Anthocyans-rich Aronia melanocarpa extract possesses ability to protect endothelial progenitor cells against angiotensin II induced dysfunction.

PubMed

Parzonko, Andrzej; Oświt, Aleksandra; Bazylko, Agnieszka; Naruszewicz, Marek

2015-12-15

Endothelial progenitor cells (EPC) may provide protection against atherosclerosis and plaque rupture by their innate ability to replace dysfunctional or damaged endothelial cells in plaque microvessels. There is evidence that angiotensin II may impair the angiogenic functions of EPCs in the atherosclerotic plaque by accelerating senescence and inhibiting their proliferation through oxidative stress induction. In this study, we examined whether chokeberry (Aronia melanocarpa) fruit extract, containing mainly anthocyanins with potent antioxidative properties, could protect EPCs against angiotensin-induced oxidative stress. EPCs were isolated from peripheral blood of young healthy volunteers and cultivated on fibronectin-coated plates in the presence or absence of angiotensin II (1 µM) and chokeberry extract (1-25 µg/ml). EPCs exposed to chokeberry extract prior to angiotensin II showed a significant increase of proliferation and telomerase activity, and a decrease in the percentage of senescent cells and intracellular ROS formation in comparison to angiotensin II treated cells. Furthermore, extract increased migration ability, adhesion to fibronectin and the angiogenic potential of EPC in vitro diminished by angiotensin II in a concentration-dependent manner. That effect was related to the activation of the Nrf2 transcription factor and the increase of HO-1 expression. Our results suggested that chokeberry extract may protect EPCs against angiotensin II-induced dysfunction and could play a potential role in the prevention of coronary artery disease. Copyright © 2015 Elsevier GmbH. All rights reserved.

Activation of peroxisome proliferator-activated receptor δ inhibits angiotensin II-induced activation of matrix metalloproteinase-2 in vascular smooth muscle cells.

PubMed

Ham, Sun Ah; Lee, Hanna; Hwang, Jung Seok; Kang, Eun Sil; Yoo, Taesik; Paek, Kyung Shin; Do, Jeong Tae; Park, Chankyu; Oh, Jae-Wook; Kim, Jin-Hoi; Han, Chang Woo; Seo, Han Geuk

2014-01-01

We investigated the role of peroxisome proliferator-activated receptor (PPAR) δ on angiotensin (Ang) II-induced activation of matrix metalloproteinase (MMP)-2 in vascular smooth muscle cells (VSMCs). Activation of PPARδ by GW501516, a specific ligand for PPARδ, attenuated Ang II-induced activation of MMP-2 in a concentration-dependent manner. GW501516 also inhibited the generation of reactive oxygen species in VSMCs treated with Ang II. A marked increase in the mRNA levels of tissue inhibitor of metalloproteinase (TIMP)-2 and -3, endogenous antagonists of MMPs, was also observed in GW501516-treated VSMCs. These effects were markedly reduced in the presence of siRNAs against PPARδ, indicating that the effects of GW501516 are PPARδ dependent. Among the protein kinases inhibited by GW501516, suppression of phosphatidylinositol 3-kinase/Akt signaling was shown to have the greatest effect on activation of MMP-2 in VSMCs treated with Ang II. Concomitantly, GW501516-mediated inhibition of MMP-2 activation in VSMCs treated with Ang II was associated with the suppression of cell migration to levels approaching those in cells not exposed to Ang II. Thus, activation of PPARδ confers resistance to Ang II-induced degradation of the extracellular matrix by upregulating expression of its endogenous inhibitor TIMP and thereby modulating cellular responses to Ang II in vascular cells. © 2014 S. Karger AG, Basel.

Cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiology.

PubMed

Jennings, Brett L; Sahan-Firat, Seyhan; Estes, Anne M; Das, Kanak; Farjana, Nasreen; Fang, Xiao R; Gonzalez, Frank J; Malik, Kafait U

2010-10-01

Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study showing that angiotensin II-induced vascular smooth muscle cell growth depends on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg per minute) or mice (1000 μg/kg per day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased vascular reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor 2,3',4,5'-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1(-/-) mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3',4,5'-tetramethoxystilbene, which prevents both cytochrome P450 1B1-dependent and -independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases.

CYTOCHROME P450 1B1 CONTRIBUTES TO ANGIOTENSIN II-INDUCED HYPERTENSION AND ASSOCIATED PATHOPHYSIOLOGY

PubMed Central

Jennings, Brett L.; Sahan-Firat, Seyhan; Estes, Anne M.; Das, Kanak; Farjana, Nasreen; Fang, Xiao R.; Gonzalez, Frank J.; Malik, Kafait U.

2010-01-01

Hypertension is the leading cause of cardiovascular diseases, and angiotensin II is one of the major components of the mechanisms that contribute to the development of hypertension. However, the precise mechanisms for the development of hypertension are unknown. Our recent study that angiotensin II-induced vascular smooth muscle cell growth is dependent on cytochrome P450 1B1 led us to investigate its contribution to hypertension caused by this peptide. Angiotensin II was infused via miniosmotic pump into rats (150 ng/kg/min) or mice (1000 μg/kg/day) for 13 days resulting in increased blood pressure, increased cardiac and vascular hypertrophy, increased vascular reactivity to vasoconstrictor agents, increased reactive oxygen species production, and endothelial dysfunction in both species. The increase in blood pressure and associated pathophysiological changes were minimized by the cytochrome P450 1B1 inhibitor, 2,3′,4,5′-tetramethoxystilbene in both species and was markedly reduced in Cyp1b1-/- mice. These data suggest that cytochrome P450 1B1 contributes to angiotensin II-induced hypertension and associated pathophysiological changes. Moreover, 2,3′,4,5′-tetramethoxystilbene which prevents both cytochrome P450 1B1-dependent and independent components of angiotensin II-induced hypertension and inhibits associated pathophysiological changes could be clinically useful in the treatment of hypertension and associated cardiovascular and inflammatory diseases. PMID:20805442

Angiotensin II up-regulates PAX2 oncogene expression and activity in prostate cancer via the angiotensin II type I receptor.

PubMed

Bose, Sudeep K; Gibson, Willietta; Giri, Shailendra; Nath, Narender; Donald, Carlton D

2009-09-01

Paired homeobox 2 gene (PAX2) is a transcriptional regulator, aberrantly expressed in prostate cancer cells and its down-regulation promotes cell death in these cells. The molecular mechanisms of tumor progression by PAX2 over-expression are still unclear. However, it has been reported that angiotensin-II (A-II) induces cell growth in prostate cancer via A-II type 1 receptor (AT1R) and is mediated by the phosphorylation of mitogen activated protein kinase (MAPK) as well as signal transducer and activator of transcription 3 (STAT3). Here we have demonstrated that A-II up-regulates PAX2 expression in prostate epithelial cells and prostate cancer cell lines resulting in increased cell growth. Furthermore, AT1R receptor antagonist losartan was shown to inhibit A-II induced PAX2 expression in prostate cancer. Moreover, analysis using pharmacological inhibitors against MEK1/2, ERK1/2, JAK-II, and phospho-STAT3 demonstrated that AT1R-mediated stimulatory effect of A-II on PAX2 expression was regulated in part by the phosphorylation of ERK1/2, JAK II, and STAT3 pathways. In addition, we have showed that down-regulation of PAX2 by an AT1R antagonist as well as JAK-II and STAT3 inhibitors suppress prostate cancer cell growth. Collectively, these findings show for the first time that the renin-angiotensin system (RAS) may promote prostate tumorigenesis via up-regulation of PAX2 expression. Therefore, PAX2 may be a novel therapeutic target for the treatment of carcinomas such as prostate cancer via the down-regulation of its expression by targeting the AT1R signaling pathways.

Angiotensin II for the Treatment of Vasodilatory Shock.

PubMed

Khanna, Ashish; English, Shane W; Wang, Xueyuan S; Ham, Kealy; Tumlin, James; Szerlip, Harold; Busse, Laurence W; Altaweel, Laith; Albertson, Timothy E; Mackey, Caleb; McCurdy, Michael T; Boldt, David W; Chock, Stefan; Young, Paul J; Krell, Kenneth; Wunderink, Richard G; Ostermann, Marlies; Murugan, Raghavan; Gong, Michelle N; Panwar, Rakshit; Hästbacka, Johanna; Favory, Raphael; Venkatesh, Balasubramanian; Thompson, B Taylor; Bellomo, Rinaldo; Jensen, Jeffrey; Kroll, Stew; Chawla, Lakhmir S; Tidmarsh, George F; Deane, Adam M

2017-08-03

Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

PubMed Central

Zhang, Wei-Wei; Bai, Feng; Wang, Jin; Zheng, Rong-Hua; Yang, Li-Wang; James, Erskine A; Zhao, Zhi-Qing

2017-01-01

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p<0.05) and ejection fraction (82%±3% vs 60%±5%, p<0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor.

PubMed

Zhang, Wei-Wei; Bai, Feng; Wang, Jin; Zheng, Rong-Hua; Yang, Li-Wang; James, Erskine A; Zhao, Zhi-Qing

2017-01-01

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p <0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p <0.05) and ejection fraction (82%±3% vs 60%±5%, p <0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension.

PubMed

Hong, Mo-Na; Li, Xiao-Dong; Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-10-18

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement.

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

PubMed Central

Chen, Dong-Rui; Ruan, Cheng-Chao; Xu, Jian-Zhong; Chen, Jing; Wu, Yong-Jie; Ma, Yu; Zhu, Ding-Liang; Gao, Ping-Jin

2016-01-01

The sympathetic nervous system interacts with the renin-angiotensin-aldosterone system (RAAS) contributing to cardiovascular diseases. In this study, we sought to determine if renal denervation (RDN) inhibits aldosterone expression and associated cardiovascular pathophysiological changes in angiotensin II (Ang II)-induced hypertension. Bilateral RDN or SHAM operation was performed before chronic 14-day Ang II subcutaneous infusion (200ng/kg/min) in male Sprague-Dawley rats. Bilateral RDN blunted Ang II-induced hypertension and ameliorated the mesenteric vascular dysfunction. Cardiovascular hypertrophy in response to Ang II was significantly attenuated by RDN as shown by histopathology and transthoracic echocardiography. Moreover, Ang II-induced vascular and myocardial inflammation and fibrosis were suppressed by RDN with concurrent decrease in fibronectin and collagen deposition, macrophage infiltration, and MCP-1 expression. Interestingly, RDN also inhibited Ang II-induced aldosterone expression in the plasma, kidney and heart. This was associated with the reduction of calcitonin gene-related peptide (CGRP) in the adrenal gland. Ang II promoted aldosterone secretion which was partly attenuated by CGRP in the adrenocortical cell line, suggesting a protective role of CGRP in this model. Activation of transforming growth factor-β (TGF-β)/Smad and mitogen-activated protein kinases (MAPKs) signaling pathway was both inhibited by RDN especially in the heart. These results suggest that the regulation of the renal sympathetic nerve in Ang II-induced hypertension and associated cardiovascular pathophysiological changes is likely mediated by aldosterone, with CGRP involvement. PMID:27661131

Angiotensin II reduces the surface abundance of KV 1.5 channels in arterial myocytes to stimulate vasoconstriction.

PubMed

Kidd, Michael W; Bulley, Simon; Jaggar, Jonathan H

2017-03-01

Several different voltage-dependent K + (K V ) channel isoforms are expressed in arterial smooth muscle cells (myocytes). Vasoconstrictors inhibit K V currents, but the isoform selectivity and mechanisms involved are unclear. We show that angiotensin II (Ang II), a vasoconstrictor, stimulates degradation of K V 1.5, but not K V 2.1, channels through a protein kinase C- and lysosome-dependent mechanism, reducing abundance at the surface of mesenteric artery myocytes. The Ang II-induced decrease in cell surface K V 1.5 channels reduces whole-cell K V 1.5 currents and attenuates K V 1.5 function in pressurized arteries. We describe a mechanism by which Ang II stimulates protein kinase C-dependent K V 1.5 channel degradation, reducing the abundance of functional channels at the myocyte surface. Smooth muscle cells (myocytes) of resistance-size arteries express several different voltage-dependent K + (K V ) channels, including K V 1.5 and K V 2.1, which regulate contractility. Myocyte K V currents are inhibited by vasoconstrictors, including angiotensin II (Ang II), but the mechanisms involved are unclear. Here, we tested the hypothesis that Ang II inhibits K V currents by reducing the plasma membrane abundance of K V channels in myocytes. Angiotensin II (applied for 2 h) reduced surface and total K V 1.5 protein in rat mesenteric arteries. In contrast, Ang II did not alter total or surface K V 2.1, or K V 1.5 or K V 2.1 cellular distribution, measured as the percentage of total protein at the surface. Bisindolylmaleimide (BIM; a protein kinase C blocker), a protein kinase C inhibitory peptide or bafilomycin A (a lysosomal degradation inhibitor) each blocked the Ang II-induced decrease in total and surface K V 1.5. Immunofluorescence also suggested that Ang II reduced surface K V 1.5 protein in isolated myocytes; an effect inhibited by BIM. Arteries were exposed to Ang II or Ang II plus BIM (for 2 h), after which these agents were removed and

Candesartan: widening indications for this angiotensin II receptor blocker?

PubMed

Mendis, B; Page, S R

2009-08-01

Candesartan cilexetil is one of a number of drugs of the angiotensin II receptor blocker (ARB) class. Their principal mode of action involves competitive blockade of the angiotensin II type 1 receptor, thereby modulating the activity of the rennin-angiotensin-aldosterone system. Angiotensin II receptor blocker therapy has been proven to be well tolerated and effective in the management of hypertension, chronic heart failure with left ventricular dysfunction and the prevention and progression of diabetic renal disease. Candesartan is a highly potent, long-acting and selective angiotensin II type 1 receptor blocker. It was launched in 1998 for the treatment of hypertension. Its use has increased dramatically, with recently published data suggesting benefit in the treatment of stroke, heart failure, diabetic renal disease and most recently in preventing the development of or delaying the progression of diabetic retinopathy. In this article we review the literature on the use of ARB drugs in general before focusing on candesartan.

Angiotensin-(1-7) has a dual role on growth-promoting signalling pathways in rat heart in vivo by stimulating STAT3 and STAT5a/b phosphorylation and inhibiting angiotensin II-stimulated ERK1/2 and Rho kinase activity.

PubMed

Giani, Jorge F; Gironacci, Mariela M; Muñoz, Marina C; Turyn, Daniel; Dominici, Fernando P

2008-05-01

Angiotensin (ANG) II contributes to cardiac remodelling by inducing the activation of several signalling molecules, including ERK1/2, Rho kinase and members of the STAT family of proteins. Angiotensin-(1-7) is produced in the heart and inhibits the proliferative actions of ANG II, although the mechanisms of this inhibition are poorly understood. Accordingly, in the present study we examined whether ANG-(1-7) affects the ANG II-mediated activation of ERK1/2 and Rho kinase, STAT3 and STAT5a/b in rat heart in vivo. We hypothesized that ANG-(1-7) inhibits these growth-promoting pathways, counterbalancing the trophic action of ANG II. Solutions of normal saline (0.9% NaCl) containing ANG II (8 pmol kg(-1)) plus ANG-(1-7) in increasing doses (from 0.08 to 800 pmol kg(-1)) were administered via the inferior vena cava to anaesthetized male Sprague-Dawley rats. After 5 min, hearts were removed and ERK1/2, Rho kinase, STAT3 and STAT5a/b phosphorylation was determined by Western blotting using phosphospecific antibodies. Angiotensin II stimulated ERK1/2 and Rho kinase phosphorylation (2.3 +/- 0.2- and 2.1 +/- 0.2-fold increase over basal values, respectively), while ANG-(1-7) was without effect. The ANG II-mediated phosphorylation of ERK1/2 and Rho kinase was prevented in a dose-dependent manner by ANG-(1-7) and disappeared in the presence of the Mas receptor antagonist d-Ala7-ANG-(1-7). Both ANG II and ANG-(1-7) increased STAT3 and STAT5a/b phosphorylation to a similar extent (130-140% increase). The ANG-(1-7)-stimulated STAT phosphorylation was blocked by the AT(1) receptor antagonist losartan and not by d-Ala7-ANG-(1-7). Our results show a dual action of ANG-(1-7), that is, a stimulatory effect on STAT3 and 5a/b phosphorylation through AT(1) receptors and a blocking action on ANG II-stimulated ERK1/2 and Rho kinase phosphorylation through Mas receptor activation. The latter effect could be representative of a mechanism for a protective role of ANG-(1-7) in the heart by

Angiotensin II Moderately Decreases Plasmodium Infection and Experimental Cerebral Malaria in Mice.

PubMed

Gallego-Delgado, Julio; Baravian, Charlotte; Edagha, Innocent; Ty, Maureen C; Ruiz-Ortega, Marta; Xu, Wenyue; Rodriguez, Ana

2015-01-01

Angiotensin II, a peptide hormone that regulates blood pressure, has been proposed as a protective factor against cerebral malaria based on a genetic analysis. In vitro studies have documented an inhibitory effect of angiotensin II on Plasmodium growth, while studies using chemical inhibitors of angiotensin II in mice showed protection against experimental cerebral malaria but not major effects on parasite growth. To determine whether the level of angiotensin II affects Plasmodium growth and/or disease outcome in malaria, elevated levels of angiotensin II were induced in mice by intradermal implantation of osmotic mini-pumps providing constant release of this hormone. Mice were then infected with P. berghei and monitored for parasitemia and incidence of cerebral malaria. Mice infused with angiotensin II showed decreased parasitemia seven days after infection. The development of experimental cerebral malaria was delayed and a moderate increase in survival was observed in mice with elevated angiotensin II, as confirmed by decreased number of cerebral hemorrhages compared to controls. The results presented here show for the first time the effect of elevated levels of angiotensin II in an in vivo model of malaria. The decreased pathogenesis observed in mice complements a previous human genetic study, reinforcing the hypothesis of a beneficial effect of angiotensin II in malaria.

Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker.

PubMed

Kajiya, Takashi; Ho, Christopher; Wang, Jiaming; Vilardi, Ryan; Kurtz, Theodore W

2011-12-01

Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24-h blood pressure more effectively than maximally recommended doses of older ARBs. Although azilsartan is considered to be an unusually potent angiotensin II type 1 (AT1) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. We investigated pleiotropic features of azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-α (PPARα), PPARδ, leptin, adipsin, and adiponectin. The effects of azilsartan on adipocyte differentiation and gene expression were observed at concentrations of azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, azilsartan inhibited cell proliferation at concentrations as low as 1 μmol/l, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 μmol/l. Antiproliferative effects of azilsartan were also observed in cells lacking AT1 receptors. In addition, azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 h after washout of drug from the incubation media. These findings suggest that azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT1 receptors and/or reduction in blood pressure.

Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Xiao-qing; Liu, Xu, E-mail: xkliuxu@126.com; Wang, Quan-xing, E-mail: wqxejd@126.com

2015-01-01

The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transformingmore » growth factor-β1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway. - Highlights: • Angiotensin II increased atrial fibrosis and related gene expressions in mice. • Angiotensin II induced atrial fibroblasts proliferation by activating signaling pathway. • Pioglitazone reversed both aforementioned changes.« less

Lactic acid bacteria: inhibition of angiotensin converting enzyme in vitro and in vivo.

PubMed

Fuglsang, Anders; Rattray, Fergal P; Nilsson, Dan; Nyborg, Niels C B

2003-01-01

A total of 26 strains of wild-type lactic acid bacteria, mainly belonging to Lactococcus lactis and Lactobacillus helveticus, were assayed in vitro for their ability to produce a milk fermentate with inhibitory activity towards angiotensin converting enzyme (ACE). It was clear that the test strains in this study, in general, produce inhibitory substances in varying amounts. Using a spectrophotometric assay based on amino group derivatization with ortho-phthaldialdehyde as a measure of relative peptide content, it was shown that there is a significant correlation between peptide formation and ACE inhibition, indicating that peptide measurement constitutes a convenient selection method. The effect of active fermentates on in vivo ACE activity was demonstrated in normotensive rats. The pressor effect of angiotensin I (0.3 microg/kg) upon intravenous injection was significantly lower when rats were pre-fed with milks fermented using two strains of Lactobacillus helveticus. An increased response to bradykinin (10 microg/kg, intravenously injected) was observed using one of these fermented milks. It is concluded that Lactobacillus helveticus produces substances which in vivo can give rise to an inhibition of ACE. The inhibition in vivo was low compared to what can be achieved with classical ACE inhibitors. The clinical relevance of this finding is discussed. This work is the first in which an effect of fermented milk on ACE in vivo has been demonstrated, measured as decreased ability to convert angiotensin I to angiotensin II.

[Over-expression of BDNF inhibits angiotensin II-induced apoptosis of cardiomyocytes in SD rats].

PubMed

Cao, Jingli; Wu, Yingfeng; Liu, Geming; Li, Zhenlong

2018-03-01

Objective To investigate the role and molecular mechanism of brain-derived neurotrophic factor (BDNF) against the process of cardiomyocyte hypertrophy and apoptosis. Methods Cardiomyocyte hypertrophy were estabolished by angiotensin II (Ang II) in neonatal cardiomyocytes in vitro and incomplete ligature of abdominal aorta of SD rats in vivo. BDNF over-expressing recombinant vector pcDNA5-BDNF was transfected into cardiomyocytes by liposomes. Immunofluorescence staining was used to detect the effect of BDNF transfection on the surface area of myocardial cells. The effect of BDNF transfection on the apoptosis of cardiomyocytes was assayed by flow cytometry. Real-time fluorescent quantitative PCR was performed to detect the effect of over-expression of BDNF on the expressions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNAs in cardiomyocytes. Western blot assay was used to observe the changes of BDNF, ANP and BNP, calmodulin kinase 2 (CaMK2) and phosphorylated calmodulin kinase 2 (p-CaMK2), calcineurin (CaN), p-CaN, nuclear factor of activated T cells 3 (NFATC3) and p-NFATC3 protein expressions in the myocardial tissues and cardiomyocytes. Results The expression of BDNF protein increased significantly in cardiac hypertrophy animal and cell models in a time-dependent manner. Compared with the untransfected control cardiomyocytes, the surface area of cardiomyocytes, the rate of apoptosis, the levels of ANP and BNP mRNA and protein expression, the levels of p-CaMK2 and CaN protein in the BDNF over-expressed cardiomyocytes were remarkably reduced, while the level of p-NFATC3 protein rose significantly. Conclusion BDNF inhibits the apoptosis of cardiomyocytes induced by Ang II, and it plays the role by inhibiting CaMK2 and CaN signaling pathways.

Atorvastatin inhibits the apoptosis of human umbilical vein endothelial cells induced by angiotensin II via the lysosomal-mitochondrial axis.

PubMed

Chang, Ye; Li, Yuan; Ye, Ning; Guo, Xiaofan; Li, Zhao; Sun, Guozhe; Sun, Yingxian

2016-09-01

This study was aimed to evaluate lysosomes-mitochondria cross-signaling in angiotensin II (Ang II)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and whether atorvastatin played a protective role via lysosomal-mitochondrial axis. Apoptosis was detected by flow cytometry, Hoechst 33342 and AO/EB assay. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of Cathepsin D (CTSD) was suppressed by pharmacological and genetic approaches. Proteins production were measured by western blotting. Our study showed that Ang II could induce the apoptosis of HUVECs in a dose-depended and time-depended manner. Exposure to 1 μM Ang II for 24 h resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and CTSD redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. These effects were all suppressed by atorvastatin. Either pharmacological or genetic inhibition of CTSD preserved mitochondrial function and decreased apoptosis in HUVECs. Most importantly, we found that the protective effect of atorvastatin was significantly greater than pharmacological or genetic inhibition of CTSD. Finally, overexpression of CTSD without exposure to Ang II had no effect on mitochondrial function and apoptosis. Our data strongly suggested that Ang II induced apoptosis through the lysosomal-mitochondrial axis in HUVECs. Furthermore, atorvastatin played an important role in the regulation of lysosomes and mitochondria stability, resulting in an antagonistic role against Ang II on HUVECs.

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn; Zhang, Dong-Mei; Yu, Xiao-Jing

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiacmore » atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

Angiotensin II stimulates basolateral 50-pS K channels in the thick ascending limb.

PubMed

Wang, Mingxiao; Luan, Haiyan; Wu, Peng; Fan, Lili; Wang, Lijun; Duan, Xinpeng; Zhang, Dandan; Wang, Wen-Hui; Gu, Ruimin

2014-03-01

We used the patch-clamp technique to examine the effect of angiotensin II (ANG II) on the basolateral K channels in the thick ascending limb (TAL) of the rat kidney. Application of ANG II increased the channel activity and the current amplitude of the basolateral 50-pS K channel. The stimulatory effect of ANG II on the K channels was completely abolished by losartan, an inhibitor of type 1 angiotensin receptor (AT1R), but not by PD123319, an AT2R antagonist. Moreover, inhibition of phospholipase C (PLC) and protein kinase C (PKC) also abrogated the stimulatory effect of ANG II on the basolateral K channels in the TAL. This suggests that the stimulatory effect of ANG II on the K channels was induced by activating PLC and PKC pathways. Western blotting demonstrated that ANG II increased the phosphorylation of c-Src at tyrosine residue 416, an indication of c-Src activation. This effect was mimicked by PKC stimulator but abolished by calphostin C. Moreover, inhibition of NADPH oxidase (NOX) also blocked the effect of ANG II on c-Src tyrosine phosphorylation. The role of Src-family protein tyrosine kinase (SFK) in mediating the effect of ANG II on the basolateral K channel was further suggested by the experiments in which inhibition of SFK abrogated the stimulatory effect of ANG II on the basolateral 50-pS K channel. We conclude that ANG II increases basolateral 50-pS K channel activity via AT1R and that activation of AT1R stimulates SFK by a PLC-PKC-NOX-dependent mechanism.

Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia

PubMed Central

Yoshida, Tadashi; Tabony, A. Michael; Galvez, Sarah; Mitch, William E.; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

2013-01-01

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5′ AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. PMID:23769949

Meconium increases type 1 angiotensin II receptor expression and alveolar cell death.

PubMed

Rosenfeld, Charles R; Zagariya, Alexander M; Liu, Xiao-Tie; Willis, Brigham C; Fluharty, Steven; Vidyasagar, Dharmapuri

2008-03-01

The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT1R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT1R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT1R protein approximately 3-fold (p = 0.006), mRNA 29% (p = 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT1R expression >3-fold in cultured type II pneumocytes and caused concentration-dependent cell death inhibited by losartan. Meconium increases AT1R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT1R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression.

Inhibition of interleukin-1 suppresses angiotensin II-induced aortic inflammation and aneurysm formation.

PubMed

Isoda, Kikuo; Akita, Koji; Kitamura, Kenichi; Sato-Okabayashi, Yayoi; Kadoguchi, Tomoyasu; Isobe, Sarasa; Ohtomo, Fumie; Sano, Motoaki; Shimada, Kazunori; Iwakura, Yoichiro; Daida, Hiroyuki

2018-06-05

Angiotensin II (Ang II) activates components of the inflammatory cascade, which promotes hypertension and development of abdominal aortic aneurysm (AAA). This study aimed to elucidate the effects of an IL-1 receptor antagonist (IL-1Ra) and an anti-IL-1β antibody (01BSUR) on Ang II-induced AAA. Male wild-type (WT) and IL-1Ra-deficient (IL-1Ra - / - ) mice were infused with Ang II (1000 ng/kg/min) using subcutaneous osmotic pumps for 28 days. Fourteen days post-infusion, both systolic blood pressure (SBP) (Ang II-treated IL-1Ra - / - :149 ± 2 vs. Ang II-treated WT:126 ± 3 mm Hg, p < 0.001) and abdominal aortic width (0.94 ± 0.09 vs. 0.49 ± 0.03 mm, p < 0.001) were significantly higher in IL-1Ra - / - mice than in WT mice. Because 28-day infusion with Ang II in IL-1Ra -/- mice significantly increased the occurrence of fatal aortic rupture (89% vs. 6%, p < 0.0001), both types of mice were infused with Ang II for only 14 days, and histological analyses were performed at 28 days. Interestingly, AAA increased more significantly in IL-1Ra - / - mice than in WT mice (p < 0.001), although SBP did not differ at 28 days in IL-1Ra - / - and WT mice (117 ± 4 vs. 115 ± 3 mm Hg, p = 0.71 (after cessation of Ang II infusion)). Histological analyses showed numerous inflammatory cells around the abdominal aorta in IL-1Ra - / - mice, but not in WT mice. Finally, compared with IgG2a treatment, treatment with 01BSUR decreased Ang II-induced AAA in IL-1Ra - / - mice. The present study demonstrates that inhibition of IL-1β significantly suppresses AAA formation after Ang II infusion, suggesting that suppression of IL-1β may provide an additional strategy to protect against AAA in hypertensive patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro.

PubMed

Trejo-Moreno, Celeste; Méndez-Martínez, Marisol; Zamilpa, Alejandro; Jiménez-Ferrer, Enrique; Perez-Garcia, Maria Dolores; Medina-Campos, Omar N; Pedraza-Chaverri, José; Santana, María Angélica; Esquivel-Guadarrama, Fernando R; Castillo, Aida; Cervantes-Torres, Jacquelynne; Fragoso, Gladis; Rosas-Salgado, Gabriela

2018-02-28

Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs) from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II) in human microvascular endothelial cells-1 (HMEC-1) cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 μg/mL of SF1, SF2, or SF3, or 10 μmol of losartan as a control. IL-6 (Interleukin 6) concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS), and the bioavailability of nitric oxide (NO) were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 μg/mL each) was the most effective combination to inhibit the production of IL-6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects.

Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro

PubMed Central

Trejo-Moreno, Celeste; Méndez-Martínez, Marisol; Perez-Garcia, Maria Dolores; Medina-Campos, Omar N.; Pedraza-Chaverri, José; Santana, María Angélica; Esquivel-Guadarrama, Fernando R.; Castillo, Aida; Cervantes-Torres, Jacquelynne; Fragoso, Gladis; Rosas-Salgado, Gabriela

2018-01-01

Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs) from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II) in human microvascular endothelial cells-1 (HMEC-1) cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 μg/mL of SF1, SF2, or SF3, or 10 μmol of losartan as a control. IL-6 (Interleukin 6) concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS), and the bioavailability of nitric oxide (NO) were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 μg/mL each) was the most effective combination to inhibit the production of IL-6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects. PMID:29495578

Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling

PubMed Central

Kim, Dongsoo; Aizawa, Toru; Wei, Heng; Pi, Xinchun; Rybalkin, Sergei D.; Berk, Bradford C.; Yan, Chen

2014-01-01

Angiotensin II (Ang II) and nitric oxide (NO)/natriuretic peptide (NP) signaling pathways mutually regulate each other. Imbalance of Ang II and NO/NP has been implicated in the pathophysiology of many vascular diseases. cGMP functions as a key mediator in the interaction between Ang II and NO/NP. Cyclic nucleotide phosphodiesterase 5A (PDE5A) is important in modulating cGMP signaling by hydrolyzing cGMP in vascular smooth muscle cells (VSMC). Therefore, we examined whether Ang II negatively modulates intracellular cGMP signaling in VSMC by regulating PDE5A. Ang II rapidly and transiently increased PDE5A mRNA levels in rat aortic VSMC. Upregulation of PDE5A mRNA was associated with a time-dependent increase of both PDE5 protein expression and activity. Increased PDE5A mRNA level was transcription-dependent and mediated by the Ang II type 1 receptor. Ang II-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was essential for Ang II-induced PDE5A upregulation. Pretreatment of VSMC with Ang II inhibited C-type NP (CNP) stimulated cGMP signaling, such as cGMP dependent protein kinase (PKG)-mediated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP). Ang II-mediated inhibition of PKG was blocked when PDE5 activity was decreased by selective PDE5 inhibitors, suggesting that upregulation of PDE5A expression is an important mechanism for Ang II to attenuate cGMP signaling. PDE5A may also play a critical role in the growth promoting effects of Ang II because inhibition of PDE5A activity significantly decreased Ang II-stimulated VSMC growth. These observations establish a new mechanism by which Ang II antagonizes cGMP signaling and stimulates VSMC growth. PMID:15623434

Inhibiting renin angiotensin system in rate limiting step by aliskiren as a new approach for preventing indomethacin induced gastric ulcers.

PubMed

Halici, Zekai; Polat, Beyzagul; Cadirci, Elif; Topcu, Atilla; Karakus, Emre; Kose, Duygu; Albayrak, Abdulmecit; Bayir, Yasin

2016-10-25

Previously blocking the renin angiotensin system (RAAS) has been effective in the prevention of gastric damage. Therefore, the aim of this study was to investigate the effects of aliskiren, and thus, direct renin blockage, in indomethacin-induced gastric damage model. Effects of aliskiren were evaluated in indomethacin-induced gastric damage model on Albino Wistar rats. Effects of famotidine has been investigated as standard antiulcer agent. Stereological analyses for ulcer area determination, biochemical analyses for oxidative status determination and molecular analyses for tissue cytokine and cyclooxygenase determination were performed on stomach tissues. In addition, to clarify antiulcer effect mechanism of aliskiren pylorus ligation-induced gastric acid secretion model was applied on rats. Aliskiren was able to inhibit indomethacin-induced ulcer formation. It also inhibited renin, and thus, decreased over-produced Angiotensin-II during ulcer formation. Aliskiren improved the oxidative status and cytokine profile of the stomach, which was most probably impaired by increased Angiotensin II concentration. Aliskiren also increased gastroprotective prostaglandin E2 concentration. Finally, aliskiren did not change the gastric acidity in pylorus ligation model. Aliskiren exerted its protective effects on stomach tissue by decreasing inflammatory cytokines and oxidative stress as a result of inhibiting the RAAS, at a rate-limiting step, as well as its end product, angiotensin II. Aliskiren also significantly increased protective factors such as PGE2, but not affect aggressive factors such as gastric acidity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients.

PubMed

Ogawa, Hisao; Kim-Mitsuyama, Shokei; Matsui, Kunihiko; Jinnouchi, Tomio; Jinnouchi, Hideaki; Arakawa, Kikuo

2012-10-01

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02). The angiotensin II receptor blocker and

Angiotensin II in Refractory Septic Shock.

PubMed

Antonucci, Elio; Gleeson, Patrick J; Annoni, Filippo; Agosta, Sara; Orlando, Sergio; Taccone, Fabio Silvio; Velissaris, Dimitrios; Scolletta, Sabino

2017-05-01

Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin-angiotensin-aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

Angiotensin II inhibits uptake of transferrin-bound iron but not non-transferrin-bound iron by cultured astrocytes.

PubMed

Huang, Suna; Du, Fang; Li, Lan; Liu, Yong; Liu, Yuhong; Zhang, Chao; Qian, Zhong Ming

2014-06-01

The existence of all components of the renin-angiotensin system (RAS) and the iron metabolism system, and the recent findings on the functions of angiotensin II (ANGII) in peripheral iron metabolism imply that ANGII might play a role in iron homeostasis by regulating expression of iron transport proteins in the brain. Here, we investigated effects of ANGII on uptake and release of iron as well as expression of cell iron transport proteins in cultured astrocytes. We demonstrated that ANGII could significantly inhibit transferrin-bound iron (Tf-Fe) uptake and iron release as well as the expression of transferrin receptor 1 (TfR1) and the iron exporter ferroportin 1 (Fpn1) in cultured astrocytes. This indicated that the inhibitory role of ANGII on Tf-Fe uptake and iron release is mediated by its negative effect on the expression of TfR1 and Fpn1. We also provided evidence that ANGII had no effect on divalent metal transporter 1 (DMT1) expression as well as non-transferrin-bound iron (NTBI) uptake in the cells. Our findings showed that ANGII has a role to affect expression of iron transport proteins in astrocytes in vitro and also suggested that ANGII might have a physiological function in brain iron homeostasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Thrombospondin-1 and Angiotensin II Inhibit Soluble Guanylyl Cyclase through an Increase in Intracellular Calcium Concentration

PubMed Central

Ramanathan, Saumya; Mazzalupo, Stacy; Boitano, Scott; Montfort, William R.

2011-01-01

Nitric Oxide (NO) regulates cardiovascular hemostasis by binding to soluble guanylyl cyclase (sGC), leading to cGMP production, reduced cytosolic calcium concentration ([Ca2+]i) and vasorelaxation. Thrombospondin-1 (TSP-1), a secreted matricellular protein, was recently discovered to inhibit NO signaling and sGC activity. Inhibition of sGC requires binding to cell-surface receptor CD47. Here, we show that a TSP-1 C-terminal fragment (E3CaG1) readily inhibits sGC in Jurkat T cells, and that inhibition requires an increase in [Ca2+]i. Using flow cytometry, we show that E3CaG1 binds directly to CD47 on the surface of Jurkat T cells. Using digital imaging microscopy on live cells, we further show that E3CaG1 binding results in a substantial increase in [Ca2+]i, up to 300 nM. Addition of angiotensin II, a potent vasoconstrictor known to increase [Ca2+]i, also strongly inhibits sGC activity. sGC isolated from calcium-treated cells or from cell-free lysates supplemented with Ca2+ remains inhibited, while addition of kinase inhibitor staurosporine prevents inhibition, indicating inhibition is likely due to phosphorylation. Inhibition is through an increase in Km for GTP, which rises to 834 µM for the NO-stimulated protein, a 13-fold increase over the uninhibited protein. Compounds YC-1 and BAY 41-2272, allosteric stimulators of sGC that are of interest for treating hypertension, overcome E3CaG1-mediated inhibition of NO-ligated sGC. Taken together, these data suggest that sGC not only lowers [Ca2+]i in response to NO, inducing vasodilation, but is also inhibited by high [Ca2+]i, providing a fine balance between signals for vasodilation and vasoconstriction. PMID:21823650

Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.

PubMed

Yoshida, Tadashi; Tabony, A Michael; Galvez, Sarah; Mitch, William E; Higashi, Yusuke; Sukhanov, Sergiy; Delafontaine, Patrice

2013-10-01

Cachexia is a serious complication of many chronic diseases, such as congestive heart failure (CHF) and chronic kidney disease (CKD). Many factors are involved in the development of cachexia, and there is increasing evidence that angiotensin II (Ang II), the main effector molecule of the renin-angiotensin system (RAS), plays an important role in this process. Patients with advanced CHF or CKD often have increased Ang II levels and cachexia, and angiotensin-converting enzyme (ACE) inhibitor treatment improves weight loss. In rodent models, an increase in systemic Ang II leads to weight loss through increased protein breakdown, reduced protein synthesis in skeletal muscle and decreased appetite. Ang II activates the ubiquitin-proteasome system via generation of reactive oxygen species and via inhibition of the insulin-like growth factor-1 signaling pathway. Furthermore, Ang II inhibits 5' AMP-activated protein kinase (AMPK) activity and disrupts normal energy balance. Ang II also increases cytokines and circulating hormones such as tumor necrosis factor-α, interleukin-6, serum amyloid-A, glucocorticoids and myostatin, which regulate muscle protein synthesis and degradation. Ang II acts on hypothalamic neurons to regulate orexigenic/anorexigenic neuropeptides, such as neuropeptide-Y, orexin and corticotropin-releasing hormone, leading to reduced appetite. Also, Ang II may regulate skeletal muscle regenerative processes. Several clinical studies have indicated that blockade of Ang II signaling via ACE inhibitors or Ang II type 1 receptor blockers prevents weight loss and improves muscle strength. Thus the RAS is a promising target for the treatment of muscle atrophy in patients with CHF and CKD. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. Copyright © 2013 Elsevier Ltd. All rights reserved.

Enhanced angiotensin-converting enzyme activity and systemic reactivity to angiotensin II in normotensive rats exposed to a high-sodium diet

PubMed Central

Crestani, Sandra; Júnior, Arquimedes Gasparotto; Marques, Maria C.A.; Sullivan, Jennifer C.; Webb, R. Clinton; da Silva-Santos, J. Eduardo

2016-01-01

A high salt diet is associated with reduced activity of the renin–angiotensin–aldosterone system (RAAS). However, normotensive rats exposed to high sodium do not show changes in systemic arterial pressure. We hypothesized that, despite the reduced circulating amounts of angiotensin II induced by a high salt diet, the cardiovascular system’s reactivity to angiotensin II is increased in vivo, contributing to maintain arterial pressure at normal levels. Male Wistar rats received chow containing 0.27% (control), 2%, 4%, or 8% NaCl for six weeks. The high-sodium diet did not lead to changes in arterial pressure, although plasma levels of angiotensin II and aldosterone were reduced in the 4% and 8% NaCl groups. The 4% and 8% NaCl groups showed enhanced pressor responses to angiotensin I and II, accompanied by unchanged and increased angiotensin-converting enzyme activity, respectively. The 4% NaCl group showed increased expression of angiotensin II type 1 receptors and reduced expression of angiotensin II type 2 receptors in the aorta. In addition, the hypotensive effect of losartan was reduced in both 4% and 8% NaCl groups. In conclusion these results explain, at least in part, why the systemic arterial pressure is maintained at normal levels in non-salt sensitive and healthy rats exposed to a high salt diet, when the functionality of RAAS appears to be blunted, as well as suggest that angiotensin II has a crucial role in the vascular dysfunction associated with high salt intake, even in the absence of hypertension. PMID:24321189

Safflor yellow B suppresses angiotensin II-mediated human umbilical vein cell injury via regulation of Bcl-2/p22{sup phox} expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Chaoyun; He, Yanhao; Department of Pharmacology, Xi'an Jiaotong University School of Medicine, Key Laboratory of Environment and Genes Related to Disease, Ministry of Education, Xi'an, Shaanxi 710061

Intracellular reactive oxygen species (ROS) are derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Angiotensin II (Ang II) can cause endothelial dysfunction by promoting intracellular ROS generation. Safflor yellow B (SYB) effectively inhibits ROS generation by upregulating Bcl-2 expression. In this study, we examined the effects of SYB on Ang II-induced injury to human umbilical vein endothelial cells (HUVECs), and elucidated the roles of NADPH oxidase and Bcl-2. We treated cultured HUVECs with Ang II, SYB, and Bcl-2 siRNA, and determined NADPH oxidase activity and ROS levels. Furthermore, cellular and mitochondrial physiological states were evaluated, and the expression levels ofmore » target proteins were analyzed. Ang II significantly enhanced intracellular ROS levels, caused mitochondrial membrane dysfunction, and decreased cell viability, leading to apoptosis. This was associated with increased expression of AT1R and p22{sup phox}, increased NADPH oxidase activity, and an increased ratio of Bax/Bcl-2, leading to decreases in antioxidant enzyme activities, which were further strengthened after blocking Bcl-2. Compared to Ang II treatment alone, co-treatment with SYB significantly reversed HUVEC injury. Taken together, these results demonstrate that SYB could significantly protect endothelial cells from Ang II-induced cell damage, and that it does so by upregulating Bcl-2 expression and inhibiting ROS generation. - Highlights: • Angiotensin II depresses mitochondria physiological function. • Angiotensin II activates NADPH oxidase via up-regulating expresion of p22{sup phox}. • Bcl-2 plays a pivotal role in improving mitochondria function and regulates ROS level. • Inhibitor of Bcl-2 promotes angiotensin II mediated HUVEC injury. • SYB attenuates angiotensin II mediated HUVEC injury via up regulating Bcl-2 expression.« less

Protein kinase C epsilon mediates the inhibition of angiotensin II on the slowly activating delayed-rectifier potassium current through channel phosphorylation.

PubMed

Gou, Xiangbo; Wang, Wenying; Zou, Sihao; Qi, Yajuan; Xu, Yanfang

2018-03-01

The slowly activating delayed rectifier K + current (I Ks ) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates I Ks through the protein kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of I Ks by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record I Ks in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited I Ks in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1-2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human I Ks in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on I Ks and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism

Angiotensin II mediated signal transduction. Important role of tyrosine kinases.

PubMed

Haendeler, J; Berk, B C

2000-11-24

It has been 100 years since the discovery of renin by Bergman and Tigerstedt. Since then, numerous studies have advanced our understanding of the renin-angiotensin system. A remarkable aspect was the discovery that angiotensin II (AngII) is the central product of the renin-angiotensin system and that this octapeptide induces multiple physiological responses in different cell types. In addition to its well known vasoconstrictive effects, growing evidence supports the notion that AngII may play a central role not only in hypertension, but also in cardiovascular and renal diseases. Binding of AngII to the seven-transmembrane angiotensin II type 1 receptor is responsible for nearly all of the physiological actions of AngII. Recent studies underscore the new concept that activation of intracellular second messengers by AngII requires tyrosine phosphorylation. An increasing number of tyrosine kinases have been shown to be activated by AngII, including the Src kinase family, the focal adhesion kinase family, the Janus kinases and receptor tyrosine kinases. These actions of AngII contribute to the pathophysiology of cardiac hypertrophy and remodeling, vascular thickening, heart failure and atherosclerosis. In this review, we discuss the important role of tyrosine kinases in AngII-mediated signal transduction. Understanding the importance of tyrosine phosphorylation in AngII-stimulated signaling events may contribute to new therapies for cardiovascular and renal diseases.

Inhibition of endoplasmic reticulum stress by intermedin1-53 attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE KO Mice.

PubMed

Ni, Xian-Qiang; Lu, Wei-Wei; Zhang, Jin-Sheng; Zhu, Qing; Ren, Jin-Ling; Yu, Yan-Rong; Liu, Xiu-Ying; Wang, Xiu-Jie; Han, Mei; Jing, Qing; Du, Jie; Tang, Chao-Shu; Qi, Yong-Fen

2018-06-26

Endoplasmic reticulum stress (ERS) is involved in the development of abdominal aortic aneurysm (AAA). Since bioactive peptide intermedin (IMD)1-53 protects against AAA formation, here we investigated whether IMD1-53 attenuates AAA by inhibiting ERS. AAA model was induced by angiotensin II (AngII) in ApoE KO mouse background. AngII-treated mouse aortas showed increased ERS gene transcription of caspase12, eukaryotic translation initiation factor 2a (eIf2a) and activating transcription factor 4(ATF4).The protein level of ERS marker glucose regulated protein 94(GRP94), ATF4 and C/EBP homologous protein 10(CHOP) was also up-regulated by AngII. Increased ERS levels were accompanied by severe VSMC apoptosis in human AAA aorta. In vivo administration of IMD1-53 greatly reduced AngII-induced AAA and abrogated the activation of ERS. To determine whether IMD inhibited AAA by ameliorating ERS, we used 2 non-selective ERS inhibitors phenyl butyrate (4-PBA) and taurine (TAU). Similar to IMD, PBA, and TAU significantly reduced the incidence of AAA and AAA-related pathological disorders. In vitro, AngII infusion up-regulated CHOP, caspase12 expression and led to VSMC apoptosis. IMD siRNA aggravated the CHOP, caspase12-mediated VSMC apoptosis, which was abolished by ATF4 silencing. IMD infusion promoted the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) in aortas in ApoE KO mice, and the AMPK inhibitor compound C abolished the protective effect of IMD on VSMC ERS and apoptosis induced by AngII. In conclusion, IMD may protect against AAA formation by inhibiting ERS via activating AMPK phosphorylation.

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

PubMed Central

Chauhan, Vikash P.; Martin, John D.; Liu, Hao; Lacorre, Delphine A.; Jain, Saloni R.; Kozin, Sergey V.; Stylianopoulos, Triantafyllos; Mousa, Ahmed S.; Han, Xiaoxing; Adstamongkonkul, Pichet; Popović, Zoran; Huang, Peigen; Bawendi, Moungi G.; Boucher, Yves; Jain, Rakesh K.

2013-01-01

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics. PMID:24084631

Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in breast cancer cells.

PubMed

Cambados, Nadia; Walther, Thomas; Nahmod, Karen; Tocci, Johanna M; Rubinstein, Natalia; Böhme, Ilka; Simian, Marina; Sampayo, Rocío; Del Valle Suberbordes, Melisa; Kordon, Edith C; Schere-Levy, Carolina

2017-10-24

Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, has been implicated in multiple aspects of cancer progression such as proliferation, migration, invasion, angiogenesis and metastasis. Ang-(1-7), is a biologically active heptapeptide, generated predominantly from AngII by the enzymatic activity of angiotensin converting enzyme 2. Previous studies have shown that Ang-(1-7) counterbalances AngII actions in different pathophysiological settings. In this study, we have analysed the impact of Ang-(1-7) on AngII-induced pro-tumorigenic features on normal murine mammary epithelial cells NMuMG and breast cancer cells MDA-MB-231. AngII stimulated the activation of the survival factor AKT in NMuMG cells mainly through the AT1 receptor. This PI3K/AKT pathway activation also promoted epithelial-mesenchymal transition (EMT). Concomitant treatment of NMuMG cells with AngII and Ang-(1-7) completely abolished EMT features induced by AngII. Furthermore, Ang-(1-7) abrogated AngII induced migration and invasion of the MDA-MB-231 cells as well as pro-angiogenic events such as the stimulation of MMP-9 activity and VEGF expression. Together, these results demonstrate for the first time that Ang-(1-7) counteracts tumor aggressive signals stimulated by AngII in breast cancer cells emerging the peptide as a potential therapy to prevent breast cancer progression.

MAP kinase-independent signaling in angiotensin II regulation of neuromodulation in SHR neurons.

PubMed

Yang, H; Raizada, M K

1998-09-01

Angiotensin II (Ang II), via its interaction with the angiotensin type 1 (AT1) receptor subtype, causes enhanced stimulation of norepinephrine (NE) neuromodulation. This involves increased transcription of NE transporter, tyrosine hydroxylase, and dopamine ss-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons. AT1 receptor-mediated regulation of certain signaling events (such as activation of the Ras-Raf-1-mitogen activated protein (MAP) kinase signaling pathway, nuclear translocation of transcription factors such as Fos and Jun, and the interactions of these factors with AP-1 binding sites) is involved in this NE neuromodulation (Lu et al. J Cell Biol. 1996;135:1609-1617). The aim of this study was to compare the signal transduction mechanism of Ang II regulation of NE neuromodulation in WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of the fact that AT1 receptor expression and Ang II stimulation of NE neuromodulation are higher in SHR neurons compared with WKY neurons. Despite this hyperactivity, Ang II stimulation of Ras, Raf-1, and MAP kinase activities was comparable between the neurons from WKY and SHR. Similarly, central injections of Ang II caused a comparable stimulation of MAP kinase in the hypothalamic and brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by either an MAP kinase kinase inhibitor (PD98059) or an MAP kinase antisense oligonucleotide completely attenuated the stimulatory effects of Ang II on [3H]-NE uptake, NE transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons. These treatments resulted in only 43% to 50% inhibition of [3H]-NE uptake and NE transporter and tyrosine hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE neuromodulation was completely blocked by MAP kinase inhibition in WKY neurons and only partially blocked in the SHR neurons. These observations suggest the presence of an additional signal transduction pathway involved in NE neuromodulation in SHR neurons

Src Family Kinases (SFK) Mediate Angiotensin II-Induced Myosin Light Chain Phosphorylation and Hypertension.

PubMed

Qin, Bo; Zhou, Junlan

2015-01-01

Angiotensin (Ang) II is the major bioactive peptide of the renin-angiotensin system (RAS); it contributes to the pathogenesis of hypertension by inducing vascular contraction and adverse remodeling, thus elevated peripheral resistance. Ang II also activates Src family kinases (SFK) in the vascular system, which has been implicated in cell proliferation and migration. However, the role of SFK in Ang II-induced hypertension is largely unknown. In this study, we found that administration of a SFK inhibitor SU6656 markedly lowered the level of systemic BP in Ang II-treated mice, which was associated with an attenuated phosphorylation of the smooth-muscle myosin-light-chain (MLC) in the mesenteric resistant arteries. In the cultured human coronary artery smooth muscle cells (SMCs), pretreatment with SU6656 blocked Ang II-induced MLC phosphorylation and contraction. These results for the first time demonstrate that SFK directly regulate vascular contractile machinery to influence BP. Thus our study provides an additional mechanistic link between Ang II and vasoconstriction via SFK-enhanced MLC phosphorylation in SMCs, and suggests that targeted inhibition of Src may provide a new therapeutic opportunity in the treatment of hypertension.

Effect of chronic intracerebroventricular angiotensin II infusion on vasopressin release in rats

NASA Technical Reports Server (NTRS)

Sterling, G. H.; Chee, O.; Riggs, R. V.; Keil, L. C.

1980-01-01

The effects of the chronic infusion of angiotensin II into the lateral cerebral ventricle on the release of arginine vasopressin in rats are investigated. Rats were subjected to a continuous infusion of angiotensin at a rate of 1 microgram/h for five days, during which they were offered water, isotonic saline or hypertonic saline ad libitum or 40 ml water/day, and fluid intake, changes in body weight, plasma sodium ion concentrations and plasma and pituitary arginine vasopressin levels were measured. Angiotensin II is found to increase the fluid intake of rats given isotonic saline and decrease plasma sodium ion levels with no changes in plasma or pituitary arginine vasopressin in those given water or isotonic saline. However, in rats given hypertonic saline, plasma sodium concentrations remained at control levels while plasma vasopressin increased, and in water-restricted rats the effects of angiotensin II were intermediate. Results thus demonstrate that angiotensin II-stimulated arginine vasopressin release is reduced under conditions in which plasma sodium ion concentration becomes dilute, compatible with a central role of angiotensin in the regulation of salt and water balance.

[Valsartan inhibits angiotensin II-Notch signaling of mesangial cells induced by high glucose].

PubMed

Yuan, Qin; Lyu, Chuan; Wu, Can; Lei, Sha; Shao, Ying; Wang, Qiuyue

2016-01-01

To explore the role of angiotensin II (Ang II)-Notch signaling in high glucose-induced secretion of extracellular matrix of rat mesangial cells (RMCs) and to further investigate the protective effect of valsartan (one of Ang II receptor blockers) on kidney. Subcultured RMCs were divided into groups as follows: normal glucose group (5.5 mmol/L glucose); high glucose group (30 mmol/L glucose); high concentration of mannitol as osmotic control group (5.5 mmol/L glucose and 24.5 mmol/L mannitol); normal glucose plus 1 μmol/L N-[N-(3, 5-difluorophenacetyl)-L-alanyl ]-S-phenylglycine t-butyl ester (DAPT) group; normal glucose plus (1, 5, 10) μmol/L valsartan group; high glucose plus 1 μmol/L DAPT group; high glucose plus (1, 5, 10) μmol/L valsartan group. Cells and supernatants were harvested after 12, 24 and 48 hours. Notch1 expression was examined by Western blotting. Secretion of transforming growth factor (TGF-β) and fibronectin (FN) were detected by ELISA. Compared to the normal glucose group, Notch1 expression was elevated in the high glucose group after 12 hours, and peaked at 24 hours. Besides, secretion of TGF-β and FN were much higher in the high glucose group than in the normal glucose group in a time-dependent manner. Compared to the untreated group, Notch1 expression decreased in a dose-dependent manner in the valsartan or DAPT treated group under high glucose after 24 hours. After pre-treatment by either valsartan or DAPT in the high glucose group, secretion of TGF-β and FN obviously decreased as compared to the untreated group. Hyperglycemia could stimulate activation of Notch signaling in cultured RMCs, which may increase secretion of downstream fibrotic factors such as TGF-β and FN. Valsartan may decrease the secretion of downstream FN in a dose-dependent manner via inhibiting AngII-Notch signaling.

Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture

NASA Technical Reports Server (NTRS)

Wada, H.; Zile, M. R.; Ivester, C. T.; Cooper, G. 4th; McDermott, P. J.

1996-01-01

The purposes of this study were 1) to determine whether angiotensin II causes growth of adult feline cardiocytes in long-term culture, 2) to compare the growth effects of angiotensin II with those resulting from electrically stimulated contraction, and 3) to determine whether the anabolic effects of contraction are exerted via the angiotensin type 1 receptor. Adult feline cardiocytes were cultured on laminin-coated trays in a serum-free medium. Cardiocytes were either electrically stimulated to contract (1 Hz, 5-ms pulse duration, alternating polarity) or were nonstimulated and quiescent. Quiescent cells were studied as controls and after treatment with angiotensin II (10(-8) M), losartan (10(-6) M; an angiotensin type 1-receptor antagonist), or angiotensin II plus losartan. Contracting cells were studied in the presence and absence of angiotensin II or losartan. In quiescent cardiocytes, angiotensin II treatment on day 7 significantly increased protein synthesis rates by 22% and protein content per cell by 17%. The effects of angiotensin II were completely blocked by losartan. Electrically stimulated contraction on days 4 and 7 in culture significantly increased protein synthesis rate by 18 and 38% and protein content per cell by 19 and 46%, respectively. Angiotensin II treatment did not further increase protein synthesis rate or protein content in contracting cardiocytes. Furthermore, losartan did not block the anabolic effects of contraction on protein synthesis rates or protein content. In conclusion, angiotensin II can exert a modest anabolic effect on adult feline cardiocytes in culture. In contracting feline cardiocytes, angiotensin II has no effect on growth. Growth caused by electrically stimulated contraction occurs more rapidly and is greater in magnitude than that caused by angiotensin II. Growth of contracting adult feline cardiocytes is not dependent on activation of the angiotensin receptor.

Expression of Angiotensin II and Aldosterone in Radiation-induced Lung Injury.

PubMed

Cao, Shuo; Wu, Rong

2012-12-01

Radiation-induced lung injury (RILI) is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILI was studied. Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-β1, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.

AT1 receptors mediate angiotensin II-induced release of nitric oxide in afferent arterioles.

PubMed

Patzak, Andreas; Lai, En Y; Mrowka, Ralf; Steege, Andreas; Persson, Pontus B; Persson, A Erik G

2004-11-01

Recent studies have indicated that angiotensin II (Ang II) possibly activates the nitric oxide (NO) system. We investigated the role of AT receptor subtypes (AT-R) in mediating the Ang II-induced NO release in afferent arterioles (Af) of mice. Isolated Af of mice were perfused, and the isotonic contraction measured. Further, NO release was determined using DAF-FM, a fluorescence indicator for NO. Moreover, we qualitatively assessed the expression of AT-R at the mRNA level using reverse transcription-polymerase chain reaction (RT-PCR). Ang II reduced luminal diameters dose dependently (67.3 +/- 6.3% at 10(-6) mol/L). Inhibition of AT2-R with PD123.319 did not change the Ang II contractile response. AT1-R blockade with ZD7155 inhibited contraction. Stimulation of AT2-R during AT1-R inhibition with ZD7155, and preconstriction with norepinephrine (NE) had no influence on the diameter. Drug application via the perfusion pipette changed flow and pressure, and enhanced NO fluorescence by DeltaF = 4.0 +/- 0.4% (N= 14, background). Luminal application of Ang II (10(-7) mol/L) increased the NO fluorescence by DeltaF = 9.9 +/- 1.2% (N= 8). AT1-R blockade blunted the increase to background levels (DeltaF to 4.0 +/- 0.3%, N= 6, P < 0.05), but AT2-R blockade did not (8.1 +/- 0.9%, N= 9). L-NAME nearly abolished the Ang II effect on the NO fluorescence (DeltaF = 1.6 +/- 0.5% (N= 8). NE did not increase NO release beyond the background levels. RT-PCR showed expression of both AT1-R and AT2-R. The results indicate an Ang II-induced NO release in Af of mice, which is mediated by AT1-R. Thus, Ang II balances its own constrictor action in Af. This control mechanism is very important in view of high renin and angiotensin II concentration in the juxtaglomerular apparatus.

Response to angiotensin-converting enzyme inhibition is selectively blunted by high sodium in angiotensin-converting enzyme DD genotype: evidence for gene-environment interaction in healthy volunteers.

PubMed

Lely, A Titia; Heerspink, Hiddo J Lambers; Zuurman, Mike; Visser, Folkert W; Kocks, Menno J A; Boomsma, Frans; Navis, Gerjan

2010-12-01

Renin-angiotensin-aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype-phenotype relationship, we hypothesize gene-environment interaction between sodium-status, the response to ACEi, and ACE genotype. Thirty-five male volunteers (26 ± 9 years; II n = 6, ID n = 18, DD n = 11) were studied during placebo and ACEi (double blind, enalapril 20 mg/day) on low [7 days 50 mmol Na/day (low salt)] and high [7 days 200 mmol Na/day (high salt)] sodium, with a washout of 6 weeks in-between. After each period mean arterial pressure (MAP) was measured before and during graded infusion of angiotensin II (Ang II). During high salt, ACEi reduced MAP in II and ID, but not in DD [II: 88 (78-94) versus 76 (72-88); ID: 87 (84-91) versus 83 (79-87); both P < 0.05 and DD: 86 (82-96) versus 88 (80-90); ns, P < 0.05 between genotypes]. However, during low salt, ACEi reduced MAP in all genotype groups [II: 83 (78-89) versus 77 (72-83); ID: 88 (84-91) versus 82 (78-86); DD: 84 (80-91) versus 81 (75-85); all P < 0.05]. During high salt + ACEi, the Ang II response was blunted in DD, with an 18% rise in MAP during the highest dose versus 22 and 31% in ID and II (P < 0.05). Low salt annihilated these differences. In healthy participants, the MAP response to ACEi is selectively blunted in DD genotype during high salt, accompanied by blunted sensitivity to Ang II. Low salt corrects both abnormalities. Further analysis of this gene-environment interaction in patients may contribute to strategies for improvement of individual treatment efficacy.

CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.

PubMed

Wang, Lei; Zhang, Yun-Long; Lin, Qiu-Yue; Liu, Yu; Guan, Xu-Min; Ma, Xiao-Lei; Cao, Hua-Jun; Liu, Ying; Bai, Jie; Xia, Yun-Long; Du, Jie; Li, Hui-Hua

2018-05-21

Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition

PubMed Central

Siddiquee, K; Hampton, J; McAnally, D; May, LT; Smith, LH

2013-01-01

Background and Purpose The apelin receptor (APJ) is often co-expressed with the angiotensin II type-1 receptor (AT1) and acts as an endogenous counter-regulator. Apelin antagonizes Ang II signalling, but the precise molecular mechanism has not been elucidated. Understanding this interaction may lead to new therapies for the treatment of cardiovascular disease. Experimental Approach The physical interaction of APJ and AT1 receptors was detected by co-immunoprecipitation and bioluminescence resonance energy transfer (BRET). Functional and pharmacological interactions were measured by G-protein-dependent signalling and recruitment of β-arrestin. Allosterism and cooperativity between APJ and AT1 were measured by radioligand binding assays. Key Results Apelin, but not Ang II, induced APJ : AT1 heterodimerization forced AT1 into a low-affinity state, reducing Ang II binding. Likewise, apelin mediated a concentration-dependent depression in the maximal production of inositol phosphate (IP1) and β-arrestin recruitment to AT1 in response to Ang II. The signal depression approached a limit, the magnitude of which was governed by the cooperativity indicative of a negative allosteric interaction. Fitting the data to an operational model of allosterism revealed that apelin-mediated heterodimerization significantly reduces Ang II signalling efficacy. These effects were not observed in the absence of apelin. Conclusions and Implications Apelin-dependent heterodimerization between APJ and AT1 causes negative allosteric regulation of AT1 function. As AT1 is significant in the pathogenesis of cardiovascular disease, these findings suggest that impaired apelin and APJ function may be a common underlying aetiology. Linked Article This article is commented on by Goupil et al., pp. 1101–1103 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12040 PMID:22935142

Inhibitory effects of atropine and hexamethonium on the angiotensin II-induced contractions of rat anococcygeus smooth muscles.

PubMed

de Godoy, Márcio Augusto Fressatto; Accorsi-Mendonça, Daniela; de Oliveira, Ana Maria

2003-02-01

We have evaluated the interaction between angiotensin II (Ang II) and the cholinergic transmission in anococcygeus smooth muscles isolated from rats treated (sympathectomised group) or not (vehicle group) with reserpine and alpha-methyl-p-tyrosine. For this, we contracted the tissues with Ang II in the presence and absence of atropine and hexamethonium. Ang II induced concentration-dependent contractions, which did not undergo temporal changes in tissues isolated from both groups of rats. In the vehicle group, Ang II induced more potent contractions than in the sympathectomised group. In the sympathectomised rat group, atropine inhibited the contractions induced by Ang II in a concentration-dependent fashion with no decrease in E(max). Additionally, hexamethonium inhibited the contraction induced by Ang II in a concentration-dependent fashion with a decrease in E(max). Association of atropine and hexamethonium produced Ang II-induced curves with rightward shifts from the control curve with a decrease in E(max). Incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) reversed the effects of atropine and hexamethonium association. Conversely, in the vehicle group of rats, atropine and hexamethonium did not produce any significant effect. However, in the presence of yohimbine, atropine shifted the Ang II-induced curves to the right of the control curve with no E(max) decrease. Results suggest that there is a positive interaction between Ang II and cholinergic transmission in the rat anococcygeus smooth muscle mediated by angiotensin receptors located on pre-ganglionic cells.

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human

PubMed Central

Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Fülöp, Gábor Á.; Csató, Viktória; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Szentkirályi, István Elek; Maros, Tamás Miklós; Szerafin, Tamás; Édes, István; Papp, Zoltán; Tóth, Attila

2014-01-01

About 8% of the adult population is taking angiotensin-converting enzyme (ACE) inhibitors to treat cardiovascular disease including hypertension, myocardial infarction and heart failure. These drugs decrease mortality by up to one-fifth in these patients. We and others have reported previously that endogenous inhibitory substances suppress serum ACE activity, in vivo, similarly to the ACE inhibitor drugs. Here we have made an effort to identify this endogenous ACE inhibitor substance. ACE was crosslinked with interacting proteins in human sera. The crosslinked products were immunoprecipitated and subjected to Western blot. One of the crosslinked products was recognized by both anti-ACE and anti-HSA (human serum albumin) antibodies. Direct ACE-HSA interaction was confirmed by binding assays using purified ACE and HSA. HSA inhibited human purified (circulating) and human recombinant ACE with potencies (IC50) of 5.7±0.7 and 9.5±1.1 mg/mL, respectively. Effects of HSA on the tissue bound native ACE were tested on human saphenous vein samples. Angiotensin I evoked vasoconstriction was inhibited by HSA in this vascular tissue (maximal force with HSA: 6.14±1.34 mN, without HSA: 13.54±2.63 mN), while HSA was without effects on angiotensin II mediated constrictions (maximal force with HSA: 18.73±2.17 mN, without HSA: 19.22±3.50 mN). The main finding of this study is that HSA was identified as a potent physiological inhibitor of the ACE. The enzymatic activity of ACE appears to be almost completely suppressed by HSA when it is present in its physiological concentration. These data suggest that angiotensin I conversion is limited by low physiological ACE activities, in vivo. PMID:24691203

Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II.

PubMed

Tumlin, James A; Murugan, Raghavan; Deane, Adam M; Ostermann, Marlies; Busse, Laurence W; Ham, Kealy R; Kashani, Kianoush; Szerlip, Harold M; Prowle, John R; Bihorac, Azra; Finkel, Kevin W; Zarbock, Alexander; Forni, Lui G; Lynch, Shannan J; Jensen, Jeff; Kroll, Stew; Chawla, Lakhmir S; Tidmarsh, George F; Bellomo, Rinaldo

2018-06-01

Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. ICUs. Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). IV angiotensin II or placebo. Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.

[Effect of angiotensin II depot administration on bioelectric functional processes of the central nervous system].

PubMed

Martin, G; Baumann, H; Grieger, F

1976-01-01

Using the average evoked potential technique, angiotensin-II depot effects (1 mg implantate = 3--4 mg/kg body weight angiotensin-II) were studied neuroelectrophysiologically in reticular, hippocampal and neocrotical structures of albino rats. A multivariate variance and discriminance analysis program revealed differentiated changes of the bioelectrical processing data of the CNS. Evidence was obtained for a varying structural sensitivity of central-nervous substructures under depot administration of angiotensin-II. In later phases of angiotensin-II action, the hippocampus was characterized by an electrographic synchronization phenomenon with high-amplitude average evoked potentials. The reticular formation, and to a lesser extent the visual cortex, showed an angiotensin-induced diminution of bioelectrical excitation. However, the intensity of the change in functional CNS patterns did not always correlate with maximal blood pressure rises. The described changes of afference processing to standardized sensory stimuli, especially in hippocampal and reticular structures of the CNS foll owing angiotensin depot action, point to a central-nervous action mechanism of angiotensin-II.

A novel mechanism of angiotensin II-regulated placental vascular tone in the development of hypertension in preeclampsia.

PubMed

Gao, Qinqin; Tang, Jiaqi; Li, Na; Zhou, Xiuwen; Li, Yongmei; Liu, Yanping; Wu, Jue; Yang, Yuxian; Shi, Ruixiu; He, Axin; Li, Xiang; Zhang, Yingying; Chen, Jie; Zhang, Lubo; Sun, Miao; Xu, Zhice

2017-05-09

The present study tested the hypothesis that angiotensin II plays a role in the regulation of placental vascular tone, which contributes to hypertension in preeclampsia. Functional and molecular assays were performed in large and micro placental and non-placental vessels from humans and animals. In human placental vessels, angiotensin II induced vasoconstrictions in 78.7% vessels in 155 tests, as referenced to KCl-induced contractions. In contrast, phenylephrine only produced contractions in 3.0% of 133 tests. In non-placental vessels, phenylephrine induced contractions in 76.0% of 67 tests, whereas angiotensin II failed to produce contractions in 75 tests. Similar results were obtained in animal placental and non-placental vessels. Compared with non-placental vessels, angiotensin II receptors and β-adrenoceptors were significantly increased in placental vessels. Compared to the vessels from normal pregnancy, angiotensin II-induced vasoconstrictions were significantly reduced in preeclamptic placentas, which was associated with a decrease in angiotensin II receptors. In addition, angiotensin II and angiotensin converting enzyme in the maternal-placenta circulation in preeclampsia were increased, whereas angiotensin I and angiotensin1-7 concentrations were unchanged. The study demonstrates a selective effect of angiotensin II in maintaining placental vessel tension, which may play an important role in development of hypertension in preeclampsia.

Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved.

PubMed

Jerez, S; de Bruno, M P; Coviello, A

2001-06-01

The aim of this study was to characterize the role of the endothelium in angiotensin II-desensitization and its mechanisms of action. Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10(-9) to 2.5 x 10(-6)) to generate two cumulative dose-response curves (CDRC I and II). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment of intact rings with L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) M) did not prevent this phenomenon. However, indomethacin (10(-5) M) and miconazol (10(-6) M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10(-6) M) and cromakalim (10(-6) M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and rubbed aortic rings were treated with the K(Ca2+) blockers apamin (10(-7) M), tetraethylammonium (TEA, 10(-3) M), and iberiotoxin (10(-8) M), and the K(ATP) blocker glibenclamide (10(-5) M). In both arteries apamin, TEA, and glibenclamide abolished the tachyphylaxis without changes in the maximal response. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries. Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms. Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P450 product, which could act by increasing K(Ca2+) channel activity.

Angiotensin II inhibits iron uptake and release in cultured neurons.

PubMed

Liu, Yong; Huang, Suna; Du, Fang; Yang, Guang; Jiang, Li Rong; Zhang, Chao; Qian, Zhong-ming

2014-05-01

Based on the well-confirmed roles of angiotensin II (ANGII) in iron transport of peripheral organs and cells, the causative link of excess brain iron with and the involvement of ANGII in neurodegenerative disorders, we speculated that ANGII might also have an effect on expression of iron transport proteins in the brain. In the present study, we investigated effects of ANGII on iron uptake and release using the radio-isotope methods as well as expression of cell iron transport proteins by Western blot analysis in cultured neurons. Our findings demonstrated for the first time that ANGII significantly reduced transferrin-bound iron and non-transferrin bound iron uptake and iron release as well as expression of two major iron uptake proteins transferrin receptor 1 and divalent metal transporter 1 and the key iron exporter ferroportin 1 in cultured neurons. The findings suggested that endogenous ANGII might have a physiological significance in brain iron metabolism.

Angiotensin II and its different receptor subtypes in placenta and fetal membranes.

PubMed

Kalenga, M K; de Gasparo, M; Thomas, K; de Hertogh, R

1996-01-01

The recent discovery of a local renin-angiotensin system in trophoblastic tissues has raised many questions regarding its role in the physiology of normal gestation and its implications in the pathophysiology of hypertension during pregnancy. In this article, the authors first review the most interesting aspects of the chorioplacental renin-angiotensin system, dwelling on the tissue distribution of angiotensin II and its receptor subtypes in the placenta and fetal membranes of different species. The relationship between angiotensin II and other locally synthesized chorioplacental substances is also analysed and the therapeutic implications of phenomena observed in pregnancy-associated hypertension are discussed.

Regulation of angiotensin II-induced neuromodulation by MARCKS in brain neurons.

PubMed

Lu, D; Yang, H; Lenox, R H; Raizada, M K

1998-07-13

Angiotensin II (Ang II) exerts chronic stimulatory actions on tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DbetaH), and the norepinephrine transporter (NET), in part, by influencing the transcription of their genes. These neuromodulatory actions of Ang II involve Ras-Raf-MAP kinase signal transduction pathways (Lu, D., H. Yang, and M.K. Raizada. 1997. J. Cell Biol. 135:1609-1617). In this study, we present evidence to demonstrate participation of another signaling pathway in these neuronal actions of Ang II. It involves activation of protein kinase C (PKC)beta subtype and phosphorylation and redistribution of myristoylated alanine-rich C kinase substrate (MARCKS) in neurites. Ang II caused a dramatic redistribution of MARCKS from neuronal varicosities to neurites. This was accompanied by a time-dependent stimulation of its phosphorylation, that was mediated by the angiotensin type 1 receptor subtype (AT1). Incubation of neurons with PKCbeta subtype specific antisense oligonucleotide (AON) significantly attenuated both redistribution and phosphorylation of MARCKS. Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II-stimulated accumulation of TH and DbetaH immunoreactivities and [3H]NE uptake activity in synaptosomes. In contrast, mRNA levels of TH, DbetaH, and NET were not influenced by MARKS-AON treatment. MARCKS pep148-165, which contains PKC phosphorylation sites, inhibited Ang II stimulation of MARCKS phosphorylation and reduced the amount of TH, DbetaH, and [3H]NE uptake in neuronal synaptosomes. These observations demonstrate that phosphorylation of MARCKS by PKCbeta and its redistribution from varicosities to neurites is important in Ang II-induced synaptic accumulation of TH, DbetaH, and NE. They suggest that a coordinated stimulation of transcription of TH, DbetaH, and NET, mediated by Ras-Raf-MAP kinase followed by their transport mediated by PKCbeta-MARCKS pathway are key in persistent

Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models.

PubMed

Kusumoto, Keiji; Igata, Hideki; Ojima, Mami; Tsuboi, Ayako; Imanishi, Mitsuaki; Yamaguchi, Fuminari; Sakamoto, Hiroki; Kuroita, Takanobu; Kawaguchi, Naohiro; Nishigaki, Nobuhiro; Nagaya, Hideaki

2011-11-01

The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent. Copyright © 2011 Elsevier B.V. All rights reserved.

Elastase-2, an angiotensin II-generating enzyme, contributes to increased angiotensin II in resistance arteries of mice with myocardial infarction.

PubMed

Becari, Christiane; Silva, Marcondes A B; Durand, Marina T; Prado, Cibele M; Oliveira, Eduardo B; Ribeiro, Mauricio S; Salgado, Helio C; Salgado, Maria Cristina O; Tostes, Rita C

2017-05-01

Angiotensin II (Ang II), whose generation largely depends on angiotensin-converting enzyme (ACE) activity, mediates most of the renin-angiotensin-system (RAS) effects. Elastase-2 (ELA-2), a chymotrypsin-serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved in Ang II-generation in resistance arteries are unknown. We hypothesized that ELA-2 contributes to vascular Ang II generation and cardiac damage in mice subjected to MI. Concentration-effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA-2 knockout (ELA-2KO) mice subjected to left anterior descending coronary artery ligation (MI). MI size was similar in WT and ELA-2KO mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA-2KO mice. Ang I-induced contractions increased in WT mice subjected to MI (MI-WT) compared with sham-WT mice. No differences were observed in Ang I reactivity between arteries from ELA-2KO and ELA-2KO subjected to MI (MI-ELA-2KO). Ang I contractions increased in arteries from MI-WT versus MI-ELA-2KO mice. Chymostatin attenuated Ang I-induced vascular contractions in WT mice, but did not affect Ang I responses in ELA-2KO arteries. These results provide the first evidence that ELA-2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA-2 as a key player in ACE-independent dysregulation of the RAS. © 2017 The British Pharmacological Society.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis.

PubMed

Takemoto, Y; Sakatani, M; Takami, S; Tachibana, T; Higaki, J; Ogihara, T; Miki, T; Katsuya, T; Tsuchiyama, T; Yoshida, A; Yu, H; Tanio, Y; Ueda, E

1998-06-01

Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken. ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls. There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis. The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy.

PubMed

Yasuno, Shinji; Kuwahara, Koichiro; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakagawa, Yasuaki; Usami, Satoru; Kuwabara, Yoshihiro; Ueshima, Kenji; Harada, Masaki; Nishikimi, Toshio; Nakao, Kazuwa

2013-12-01

Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. © 2013 The British Pharmacological Society.

Gestational Protein Restriction Increases Angiotensin II Production in Rat Lung1

PubMed Central

Gao, Haijun; Yallampalli, Uma; Yallampalli, Chandra

2013-01-01

ABSTRACT Gestational protein restriction (PR) alters the renin-angiotensin system in uterine arteries and placentas and elevates plasma levels of angiotensin II in pregnant rats. To date, how PR increases maternal plasma levels of angiotensin II remains unknown. In this study, we hypothesize that the expression and/or the activity of angiotensin I converting enzyme (peptidyl-dipeptidase A) 1 (ACE) in lungs, but not kidneys and blood, largely contribute to elevated plasma angiotensin II levels in pregnant rats subject to gestational PR. Time-scheduled pregnant Sprague-Dawley rats were fed a normal or low-protein diet from Day 3 of pregnancy until euthanized at Day 19 or 22. Expressions of Ace and Ace2 (angiotens in I converting enzyme [peptidyl-dipeptidase A] 2) in lungs and kidneys from pregnant rats by quantitative real-time PCR and Western blotting, and the activities of these proteins in lungs, kidneys, and plasma, were measured. The mRNA levels of Ace and Ace2 in lungs were elevated by PR at both Days 19 and 22 of pregnancy. The abundance of ACE protein in lungs was increased, but ACE2 protein was decreased, by PR. The activities of ACE, but not ACE2, in lungs were increased by PR. PR did not change expressions of Ace and Ace2, the activities of both ACE and ACE2 in kidneys, and the abundance and activity of plasma ACE. These findings suggest that maternal lungs contribute to the elevated plasma levels of angiotensin II by increasing both the expression and the activity of ACE in response to gestational PR. PMID:23365412

Icariin attenuates angiotensin II-induced hypertrophy and apoptosis in H9c2 cardiomyocytes by inhibiting reactive oxygen species-dependent JNK and p38 pathways

PubMed Central

ZHOU, HENG; YUAN, YUAN; LIU, YUAN; DENG, WEI; ZONG, JING; BIAN, ZHOU-YAN; DAI, JIA; TANG, QI-ZHU

2014-01-01

Icariin, the major active component isolated from plants of the Epimedium family, has been reported to have potential protective effects on the cardiovascular system. However, it is not known whether icariin has a direct effect on angiotensin II (Ang II)-induced cardiomyocyte enlargement and apoptosis. In the present study, embryonic rat heart-derived H9c2 cells were stimulated by Ang II, with or without icariin administration. Icariin treatment was found to attenuate the Ang II-induced increase in mRNA expression levels of hypertrophic markers, including atrial natriuretic peptide and B-type natriuretic peptide, in a concentration-dependent manner. The cell surface area of Ang II-treated H9c2 cells also decreased with icariin administration. Furthermore, icariin repressed Ang II-induced cell apoptosis and protein expression levels of Bax and cleaved-caspase 3, while the expression of Bcl-2 was increased by icariin. In addition, 2′,7′-dichlorofluorescein diacetate incubation revealed that icariin inhibited the production of intracellular reactive oxygen species (ROS), which were stimulated by Ang II. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 in Ang II-treated H9c2 cells was blocked by icariin. Therefore, the results of the present study indicated that icariin protected H9c2 cardiomyocytes from Ang II-induced hypertrophy and apoptosis by inhibiting the ROS-dependent JNK and p38 pathways. PMID:24940396

Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

PubMed

Mercier, Kelly; Smith, Holly; Biederman, Jason

2014-12-01

Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events. Copyright © 2014 Elsevier Inc. All rights reserved.

Brain-Targeted (Pro)Renin Receptor Knockdown attenuates Angiotensin II-Dependent Hypertension

PubMed Central

Li, Wencheng; Peng, Hua; Cao, Theresa; Sato, Ryosuke; McDaniels, Sarah. J.; Kobori, Hiroyuki; Navar, L. Gabriel; Feng, Yumei

2012-01-01

The (pro)renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro)renin receptor in hypertension, adeno-associated virus-mediated (pro)renin receptor shRNA was used to knockdown (pro)renin receptor expression in the brain of non-transgenic normotensive and human renin-angiotensinogen double transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro)renin receptor, angiotensin II type 1 receptor and vasopressin mRNA levels. Plasma vasopressin levels were determined by Enzyme-Linked Immuno Sorbent Assay. Double transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro)renin receptor shRNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared to the control virus treatment in double transgenic mice. (Pro)renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double transgenic mice. These data indicate that (pro)renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease insympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro)renin receptor knockdown is associated with down-regulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro)renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. PMID:22526255

Drinking and changes in blood pressure in response to angiotensin II in the pigeon Columba livia.

PubMed

Evered, M D; Fitzsimons, J T

1981-01-01

1. Angiotensin II is as potent a stimulus to drink in pigeons as it is in mammals. There are striking similarities in the action of this peptide in pigeons and mammals. 2. Angiotensin II injected intracranially, I.V. or I.P. consistently caused short-latency and vigorous drinking in pigeons but no other behaviour. Drinking was completed rapidly and intakes were very large, sometimes in excess of 10% of the bird's body weight. 3. The latency to drink and the amount drunk were dose dependent for all routes of injection. Angiotensin II was most effective when injected directly into the brain. As little as 10(-4) mol angiotensin II injected into the cerebral ventricles caused birds to drink. 4. The rapid cessation of drinking after intracranial injection of angiotensin II was not caused by rapid loss of activity of the peptide in the brain but by the actual ingestion of the water. 5. The brain sites most sensitive to the dipsogenic action of angiotensin II in the pigeon were the dorsal and ventral third ventricle, the tissue adjacent and anterior to these sites, and the lateral ventricles. The lateral hypothalamic area was only slightly less sensitive. Negative sites for drinking were found in the lateral forebrain and the hind brain. These findings are similar to those in mammals. 6. Pigeons drank during I.V. infusion of as little as 16 X 10(-12) mol angiotensin II kg-1 min-1. This was near the threshold for increasing arterial pressure in pigeons and is near the threshold for drinking in rats and dogs. 7. The Asn1, Asp1, Val5 and Ile5 analogues of angiotensin II were equipotent as stimuli to drink but a wide range of other peptides and drugs injected into the brain failed to increase water intake. An exception was eledoisin which was, comparing molecule with molecule, only 10-100 times less potent than angiotensin II in the pigeon. 8. Injections of angiotensin II into brain sites which caused drinking failed to alter heart rate or arterial pressure in pigeons. 9

The Renin-Angiotensin System, Not the Kinin-Kallikrein System, Affects Post-Exercise Proteinuria.

PubMed

Koçer, Günnur; Basralı, Filiz; Kuru, Oktay; Şentürk, Ümit Kemal

2018-05-17

Temporary proteinuria post-exercise is common and is caused predominantly by renal haemodynamic alterations. One reason is up-regulation of angiotensin II (Ang II) due to the reducing effect of angiotensin-converting enzyme (ACE) inhibitors. However, another, ignored, reason could be the kininase effect of ACE inhibition. This study investigated how ACE inhibition reduces post-exercise proteinuria: by either Ang II up-regulation inhibition or bradykinin elevation due to kininase activity inhibition. Our study included 10 volunteers, who completed 3 high-intensity exercise protocols involving cycling at 1-week intervals. The first protocol was a control arm, the second evaluated the effect of ACE inhibition and the third examined the effect of angiotensin type 1 receptor blockade. Upon application, both agents reduced systolic and diastolic blood pressure; however, there were no statistically significant -differences. In addition, total protein, microalbumin and -β2-microglobulin excretion levels in urine specimens were analysed before, 30 min after and 120 min after the exercise protocols. Total protein levels in urine samples were elevated in all 3 protocols after 30 min of high-intensity exercise, compared to baseline levels. However, both ACE inhibition and angiotensin type 1 receptor blockade suppressed total protein in the 30th min. In each protocol, total protein levels returned to the baseline after 120 min. Urinary microalbumin and β2-microglobulin levels during the control protocol were significantly higher 30 min post-exercise; however, only angiotensin type 1 receptor blockade suppressed microalbumin levels. The results indicated Ang II up-regulation, not bradykinin elevation, plays a role in post-exercise proteinuria. © 2018 S. Karger AG, Basel.

Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis

PubMed Central

Takemoto, Y.; Sakatani, M.; Takami, S.; Tachibana, T.; Higaki, J.; Ogihara, T.; Miki, T.; Katsuya, T.; Tsuchiyama, T.; Yoshida, A.; Yu, H.; Tanio, Y.; Ueda, E.

1998-01-01

BACKGROUND—Serum angiotensin converting enzyme (SACE) is considered to reflect disease activity in sarcoidosis. SACE activity is increased in many patients with active sarcoid lesions. The mechanism for the increased SACE activity in this disease has not been clarified. ACE insertion/deletion (I/D) gene polymorphism has been reported to have an association with SACE levels in sarcoidosis, but no evidence of an association between angiotensin II receptor gene polymorphism and SACE in this disease has been found. A study of the association of angiotensin II receptor gene polymorphisms with sarcoidosis was therefore undertaken.
METHODS—ACE (I/D), angiotensin II type 1 receptor (AGTR1), and angiotensin II type 2 receptor (AGTR2 ) gene polymorphisms were investigated by polymerase chain reaction (PCR) and SACE levels were measured in three groups of patients: those with sarcoidosis or tuberculosis and normal controls.
RESULTS—There was no difference in allele frequency of AGTR1 and AGTR2 polymorphism among the three groups. Neither AGTR1 nor AGTR2 polymorphisms were associated with sarcoidosis. SACE activity was higher in patients with sarcoidosis with the AGTR1 A/C genotype than in others. However, this tendency was not detected in patients with tuberculosis.
CONCLUSIONS—The AGTR1 allele C is associated with high activity of SACE in patients with sarcoidosis. It is another predisposing factor for high levels of SACE in patients with sarcoidosis and is considered to be an independent factor from the ACE D allele for high levels of SACE in sarcoidosis. This fact could be one of the explanations for the increased SACE activity in sarcoidosis.

 PMID:9713444

Locations and properties of angiotensin II-responsive neurones in the circumventricular region of the duck brain.

PubMed Central

Matsumura, K; Simon, E

1990-01-01

1. In brain slice preparations from the hypothalamus of domestic ducks, single-unit activity was recorded extracellularly to investigate location and properties of angiotensin II (AngII)-responsive neurones in various periventricular regions. 2. When exposing the slice to 10(-7) M-AngII in the perfusion medium, more than 65% of the neurones recorded in the subfornical organ (SFO) were activated (49 out of 75) and none inhibited. In the magnocellular (MC) region of the paraventricular nucleus (PVN) only four out of eighty-one neurones were influenced by AngII; one was inhibited and three were activated. In the anterior third ventricle region (A3V) two out of twenty-one neurones were activated by AngII. In the dorsal periventricular (PeV) region, one out of thirty-seven neurones was activated and one inhibited. The changes in firing rate of AngII-responsive neurones at comparable doses of AngII were generally large in the SFO and A3V but were small in neurones from the MC and PeV regions. 3. Analysis of AngII-responsive SFO neurones consistently revealed a dose-dependent stimulation with a threshold at 10(-9) M-AngII. The AngII antagonist 1Sar-8Ile-AngII (4 x 10(-7) to 10(-6) M) caused reversible, complete or partial suppression of responsiveness to 10(-7) M-AngII. Synaptic blockade with a medium low in Ca2+ and high in Mg2+ did not abolish AngII responsiveness in eight out of ten SFO neurones tested. 4. Angiotensin III affected neither AngII-responsive nor AngII-insensitive neurones. When eighteen AngII-responsive neurones were exposed to hypertonic stimulation (+20 to +30 mosmol/kg) by adding NaCl to the perfusion medium, only one neurone was stimulated and two were inhibited. 5. The results indicate that: (a) the SFO is a specific target for circulating AngII; (b) although neurones in the A3V responsive to AngII are rare, the pronounced excitation of those which were found suggest that neurones in this region might serve as targets for AngII acting from the brain

Alpha 2-macroglobulin capture allows detection of mast cell chymase in serum and creates a reservoir of angiotensin II-generating activity.

PubMed

Raymond, Wilfred W; Su, Sharon; Makarova, Anastasia; Wilson, Todd M; Carter, Melody C; Metcalfe, Dean D; Caughey, George H

2009-05-01

Human chymase is a highly efficient angiotensin II-generating serine peptidase expressed by mast cells. When secreted from degranulating cells, it can interact with a variety of circulating antipeptidases, but is mostly captured by alpha(2)-macroglobulin, which sequesters peptidases in a cage-like structure that precludes interactions with large protein substrates and inhibitors, like serpins. The present work shows that alpha(2)-macroglobulin-bound chymase remains accessible to small substrates, including angiotensin I, with activity in serum that is stable with prolonged incubation. We used alpha(2)-macroglobulin capture to develop a sensitive, microtiter plate-based assay for serum chymase, assisted by a novel substrate synthesized based on results of combinatorial screening of peptide substrates. The substrate has low background hydrolysis in serum and is chymase-selective, with minimal cleavage by the chymotryptic peptidases cathepsin G and chymotrypsin. The assay detects activity in chymase-spiked serum with a threshold of approximately 1 pM (30 pg/ml), and reveals native chymase activity in serum of most subjects with systemic mastocytosis. alpha(2)-Macroglobulin-bound chymase generates angiotensin II in chymase-spiked serum, and it appears in native serum as chymostatin-inhibited activity, which can exceed activity of captopril-sensitive angiotensin-converting enzyme. These findings suggest that chymase bound to alpha(2)-macroglobulin is active, that the complex is an angiotensin-converting enzyme inhibitor-resistant reservoir of angiotensin II-generating activity, and that alpha(2)-macroglobulin capture may be exploited in assessing systemic release of secreted peptidases.

Sex-specific effect of endothelin in the blood pressure response to acute angiotensin II in growth-restricted rats

PubMed Central

Intapad, Suttira; Ojeda, Norma B.; Varney, Elliott; Royals, Thomas P.; Alexander, Barbara T.

2015-01-01

The renal endothelin system contributes to sex differences in blood pressure with males demonstrating greater endothelin type-A receptor-mediated responses relative to females. Intrauterine growth restriction programs hypertension and enhanced renal sensitivity to acute angiotensin II in male growth-restricted rats. Endothelin is reported to work synergistically with angiotensin II. Thus, this study tested the hypothesis that endothelin augments the blood pressure response to acute angiotensin II in male growth-restricted rats. Systemic and renal hemodynamics were determined in response to acute angiotensin II (100 nanogram/kilogram/minute for 30 minutes) with and without the endothelin type-A receptor antagonist, ABT 627(10 nanogram/kilogram/minute for 30 minutes), in rats pretreated with enalapril (250 milligram/Liter for one week) to normalize the endogenous renin angiotensin system. Endothelin type-A receptor blockade reduced angiotensin II-mediated increases in blood pressure in male control and male growth-restricted rats. Endothelin type-A receptor blockade also abolished hyper-responsiveness to acute angiotensin II in male growth-restricted rats. Yet, blood pressure remained significantly elevated above baseline following endothelin type-A receptor blockade suggesting that factors in addition to endothelin contribute to the basic angiotensin II-induced pressor response in male rats. We also determined sex-specific effects of endothelin on acute angiotensin II-mediated hemodynamic responses. Endothelin type-A receptor blockade did not reduce acute angiotensin II-mediated increases in blood pressure in female control or growth-restricted rats, intact or ovariectomized. Thus, these data suggest that endothelin type-A receptor blockade contributes to hypersensitivity to acute angiotensin II in male growth-restricted rats and further supports the sex-specific effect of endothelin on blood pressure. PMID:26459423

Candesartan cilexetil: an angiotensin II receptor blocker.

PubMed

Stoukides, C A; McVoy, H J; Kaul, A F

1999-12-01

To summarize and critique the medical literature on candesartan cilexetil, an angiotensin II receptor blocker (ARB). MEDLINE searches (January 1966-January 1999) and manufacturer prescribing literature were used to identify articles on candesartan cilexetil. Bibliographies were also reviewed for germane articles. Study and review articles describing the chemistry, human pharmacology, pharmacodynamics, pharmacokinetics, placebo-controlled trials, comparative trials, and clinical application of candesartan cilexetil based on the published literature and premarketing clinical trials were reviewed. All literature on the use of candesartan cilexetil for treating hypertension and congestive heart failure were included. ARBs are a new class of drugs with increasing use in treating hypertension. Studies are ongoing to determine the role of these agents in preventing remodeling after myocardial infarction and in patients with congestive heart failure. Candesartan cilexetil is among the newest drugs in the class that includes losartan, irbesartan, and valsartan. Candesartan cilexetil has more than 1000 times more affinity for the angiotensin II, type AT1 receptor ARBs, and the binding affinity and competitive angiotensin II receptor antagonism is stronger than that of losartan. Clinical studies in patients with hypertension have demonstrated that candesartan cilexetil, in doses of 4-16 mg, is more effective in reducing sitting diastolic blood pressure than are placebo and losartan 50 mg. Candesartan cilexetil has demonstrated reductions in blood pressure comparable to those of enalapril, with the rate of adverse events greater in the enalapril group. Dosage adjustments are not necessary in elderly patients or in patients with mild hepatic or renal dysfunction. In diabetic patients, blood glucose, hemoglobinA1c, and serum lipids are not affected. The clinical studies demonstrated that the adverse effect profile of candesartan cilexetil was similar to that of placebo and there

Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery patIents cOhort evaluatioN Prospective Cohort.

PubMed

Roshanov, Pavel S; Rochwerg, Bram; Patel, Ameen; Salehian, Omid; Duceppe, Emmanuelle; Belley-Côté, Emilie P; Guyatt, Gordon H; Sessler, Daniel I; Le Manach, Yannick; Borges, Flavia K; Tandon, Vikas; Worster, Andrew; Thompson, Alexandra; Koshy, Mithin; Devereaux, Breagh; Spencer, Frederick A; Sanders, Robert D; Sloan, Erin N; Morley, Erin E; Paul, James; Raymer, Karen E; Punthakee, Zubin; Devereaux, P J

2017-01-01

The effect on cardiovascular outcomes of withholding angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in chronic users before noncardiac surgery is unknown. In this international prospective cohort study, the authors analyzed data from 14,687 patients (including 4,802 angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users) at least 45 yr old who had in-patient noncardiac surgery from 2007 to 2011. Using multivariable regression models, the authors studied the relationship between withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and a primary composite outcome of all-cause death, stroke, or myocardial injury after noncardiac surgery at 30 days, with intraoperative and postoperative clinically important hypotension as secondary outcomes. Compared to patients who continued their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, the 1,245 (26%) angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker users who withheld their angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers in the 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P = 0.01) and intraoperative hypotension (adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001). The risk of postoperative hypotension was similar between the two groups (adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the range of preoperative blood pressures. The practice of withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers was only modestly correlated with patient characteristics and the type and timing of surgery. Withholding angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers before major noncardiac surgery

Voltage-Independent Inhibition of the Tetrodotoxin-Sensitive Sodium Currents by Oxotremorine and Angiotensin II in Rat Sympathetic Neurons.

PubMed

Puente, Erika I; De la Cruz, Lizbeth; Arenas, Isabel; Elias-Viñas, David; Garcia, David E

2016-04-01

Tetrodotoxin-sensitive Na(+) currents have been extensively studied because they play a major role in neuronal firing and bursting. In this study, we showed that voltage-dependent Na(+) currents are regulated in a slow manner by oxotremorine (oxo-M) and angiotensin II in rat sympathetic neurons. We found that these currents can be readily inhibited through a signaling pathway mediated by G proteins and phospholipase C (PLC) β1. This inhibition is slowly established, pertussis toxin-insensitive, partially reversed within tens of seconds after oxo-M washout, and not relieved by a strong depolarization, suggesting a voltage-insensitive mechanism of inhibition. Specificity of the M1 receptor was tested by the MT-7 toxin. Activation and inactivation curves showed no shift in the voltage dependency under the inhibition by oxo-M. This inhibition is blocked by a PLC inhibitor (U73122, 1-(6-{[(17β)-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino}hexyl)-1H-pyrrole-2,5-dione), and recovery from inhibition is prevented by wortmannin, a PI3/4 kinase inhibitor. Hence, the pathway involves Gq/11 and is mediated by a diffusible second messenger. Oxo-M inhibition is occluded by screening phosphatidylinositol 4,5-bisphosphate (PIP2)-negative charges with poly-l-lysine and prevented by intracellular dialysis with a PIP2 analog. In addition, bisindolylmaleimide I, a specific ATP-competitive protein kinase C (PKC) inhibitor, rules out that this inhibition may be mediated by this protein kinase. Furthermore, oxo-M-induced suppression of Na(+) currents remains unchanged when neurons are treated with calphostin C, a PKC inhibitor that targets the diacylglycerol-binding site of the kinase. These results support a general mechanism of Na(+) current inhibition that is widely present in excitable cells through modulation of ion channels by specific G protein-coupled receptors. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Effects of Angiotensin Inhibitor Valsartan on the Expression of the Angiotensin II 1 Receptor, Matrix Metalloproteinases -2 and -9 in Human Bladder Cancer Cell Lines.

PubMed

Yang, Delin; Huo, Qian; Luan, Ting; Wang, Jiansong; Tang, Zhaoran; Wang, Haifeng

2016-08-01

In order to investigate how valsartan-the angiotensin II 1 receptor (AT1R) antagonist-affects the expressions of AT1R antigen, matrix metalloproteinases (MMPs) -2 and -9 in carcinoma of urinary bladder (CUB) cell lines with different invasive abilities. Three cell lines, EJ-M3, EJ, and BIU-87, with different invasive abilities were cultured and treated with valsartan. Cell proliferation states were determined by the methyl thiazolyl tetrazolium (MTT) method. The expressions at protein level and gene level were determined by Western blot and real-time fluorescence reverse transcription polymerase chain reaction (RT-PCR), respectively. The invasive abilities and migratory abilities of the three cell lines were determined by Transwell in vitro cell invasion assay and wound healing assay, respectively. MTT results show that valsartan can inhibit the proliferation of CUB cells, and the inhibition effect is enhanced with the increase of concentration. AngII promotes the MMP2 and MMP9 expressions (both protein and gene levels) in CUB cells through AT1R, but their expressions can be effectively inhibited by valsartan, the AngII inhibitor. AngII inhibitor may become a novel drug that can inhibit CUB metastasis and prolong the survival of CUB patients.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

PubMed Central

Hubers, Scott A.; Brown, Nancy J.

2016-01-01

Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

Angiotensin II modulates salty and sweet taste sensitivities.

PubMed

Shigemura, Noriatsu; Iwata, Shusuke; Yasumatsu, Keiko; Ohkuri, Tadahiro; Horio, Nao; Sanematsu, Keisuke; Yoshida, Ryusuke; Margolskee, Robert F; Ninomiya, Yuzo

2013-04-10

Understanding the mechanisms underlying gustatory detection of dietary sodium is important for the prevention and treatment of hypertension. Here, we show that Angiotensin II (AngII), a major mediator of body fluid and sodium homeostasis, modulates salty and sweet taste sensitivities, and that this modulation critically influences ingestive behaviors in mice. Gustatory nerve recording demonstrated that AngII suppressed amiloride-sensitive taste responses to NaCl. Surprisingly, AngII also enhanced nerve responses to sweeteners, but had no effect on responses to KCl, sour, bitter, or umami tastants. These effects of AngII on nerve responses were blocked by the angiotensin II type 1 receptor (AT1) antagonist CV11974. In behavioral tests, CV11974 treatment reduced the stimulated high licking rate to NaCl and sweeteners in water-restricted mice with elevated plasma AngII levels. In taste cells AT1 proteins were coexpressed with αENaC (epithelial sodium channel α-subunit, an amiloride-sensitive salt taste receptor) or T1r3 (a sweet taste receptor component). These results suggest that the taste organ is a peripheral target of AngII. The specific reduction of amiloride-sensitive salt taste sensitivity by AngII may contribute to increased sodium intake. Furthermore, AngII may contribute to increased energy intake by enhancing sweet responses. The linkage between salty and sweet preferences via AngII signaling may optimize sodium and calorie intakes.

Angiotensin II Causes Neuronal Damage in Stretch-Injured Neurons: Protective Effects of Losartan, an Angiotensin T1 Receptor Blocker.

PubMed

Abdul-Muneer, P M; Bhowmick, Saurav; Briski, Nicholas

2017-11-08

Angiotensin II (Ang II) is a mediator of oxidative stress via activation/induction of reactive oxygen and nitrogen species-generating enzymes, NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS). We investigated the hypothesis that overproduction of Ang II during traumatic brain injury (TBI) induces the activation of the oxidative stress, which triggers neuroinflammation and cell apoptosis in a cell culture model of neuronal stretch injury. We first established that stretch injury causes a rapid increase in the level of Ang II, which causes the release of pro-inflammatory cytokines, IL-1β and TNF-α, via the induction of oxidative stress. Since angiotensin-converting enzyme (ACE) mediates the production of Ang II via the conversion of Ang I into Ang II, we analyzed the expression of ACE by western blotting. Further, we analyzed caspase-3-mediated apoptosis by TUNEL staining and annexin V western blotting. Angiotensin type I (AT 1 ) receptor antagonist losartan attenuated Ang II-induced oxidative stress and associated neuroinflammation and cell death in cultured neurons. Remarkably, we noticed that the expression of Ang II type 1 receptor (AngT 1 R) upregulated in neuronal stretch injury; losartan mitigates this upregulation. Findings from this study significantly extend our understanding of the pathophysiology of TBI and may have significant implications for developing therapeutic strategies for TBI-associated brain dysfunctions.

Vascular Induction of a Disintegrin and Metalloprotease 17 by Angiotensin II Through Hypoxia Inducible Factor 1α

PubMed Central

Obama, Takashi; Takayanagi, Takehiko; Kobayashi, Tomonori; Bourne, Allison M.; Elliott, Katherine J.; Charbonneau, Martine; Dubois, Claire M.

2015-01-01

BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. PMID:24871629

Targeting Angiotensin II Type-1 Receptor (AT1R) Inhibits the Harmful Phenotype of Plasmodium-Specific CD8+ T Cells during Blood-Stage Malaria.

PubMed

Silva-Filho, João L; Caruso-Neves, Celso; Pinheiro, Ana A S

2017-01-01

CD8 + T-cell response is critical in the pathogenesis of cerebral malaria during blood-stage. Our group and other have been shown that angiotensin II (Ang II) and its receptor AT 1 (AT 1 R), a key effector axis of renin-angiotensin system (RAS), have immune regulatory effects on T cells. Previously, we showed that inhibition of AT 1 R signaling protects mice against the lethal disease induced by Plasmodium berghei ANKA infection However, most of the Ang II/AT 1 R actions were characterized by using only pharmacological approaches, the effects of which may not always be due to a specific receptor blockade. In addition, the mechanisms of action of the AT 1 R in inducing the pathogenic activity of Plasmodium -specific CD8 + T cells during blood-stage were not determined. Here, we examined how angiotensin II/AT 1 R axis promotes the harmful response of Plasmodium -specific CD8 + T-cell during blood-stage by using genetic and pharmacological approaches. We evaluated the response of wild-type (WT) and AT 1 R -/- Plasmodium -specific CD8 + T cells in mice infected with a transgenic PbA lineage expressing ovalbumin; and in parallel infected mice receiving WT Plasmodium -specific CD8 + T cells were treated with losartan (AT 1 R antagonist) or captopril (ACE inhibitor). Both, AT 1 R -/- OT-I cells and WT OT-I cells from losartan- or captopril-treated mice showed lower expansion, reduced IL-2 production and IL-2Rα expression, lower activation (lower expression of CD69, CD44 and CD160) and lower exhaustion profiles. AT 1 R -/- OT-I cells also exhibit lower expression of the integrin LFA-1 and the chemokine receptors CCR5 and CXCR3, known to play a key role in the development of cerebral malaria. Moreover, AT 1 R -/- OT-I cells produce lower amounts of IFN-γ and TNF-α and show lower degranulation upon restimulation. In conclusion, our results show the pivotal mechanisms of AT 1 R-induced harmful phenotype of Plasmodium -specific CD8 + T cells during blood-stage malaria.

Cytosolic phospholipase A2α is critical for angiotensin II-induced hypertension and associated cardiovascular pathophysiology.

PubMed

Khan, Nayaab S; Song, Chi Young; Jennings, Brett L; Estes, Anne M; Fang, Xiao R; Bonventre, Joseph V; Malik, Kafait U

2015-04-01

Angiotensin II activates cytosolic phospholipase A(2)α (cPLA2α) and releases arachidonic acid from tissue phospholipids, which mediate or modulate ≥1 cardiovascular effects of angiotensin II and has been implicated in hypertension. Because arachidonic acid release is the rate limiting step in eicosanoid production, cPLA2α might play a central role in the development of angiotensin II-induced hypertension. To test this hypothesis, we investigated the effect of angiotensin II infusion for 13 days by micro-osmotic pumps on systolic blood pressure and associated pathogenesis in wild type (cPLA2α(+/+)) and cPLA2α(-/-) mice. Angiotensin II-induced increase in systolic blood pressure in cPLA2α(+/+) mice was abolished in cPLA2α(-/-) mice; increased systolic blood pressure was also abolished by the arachidonic acid metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid in cPLA2α(+/+) mice. Angiotensin II in cPLA2α(+/+) mice increased cardiac cPLA2 activity and urinary eicosanoid excretion, decreased cardiac output, caused cardiovascular remodeling with endothelial dysfunction, and increased vascular reactivity in cPLA2α(+/+) mice; these changes were diminished in cPLA2α(-/-) mice. Angiotensin II also increased cardiac infiltration of F4/80(+) macrophages and CD3(+) T lymphocytes, cardiovascular oxidative stress, expression of endoplasmic reticulum stress markers p58(IPK), and CHOP in cPLA2α(+/+) but not cPLA2α(-/-) mice. Angiotensin II increased cardiac activity of ERK1/2 and cSrc in cPLA2α(+/+) but not cPLA2α(-/-) mice. These data suggest that angiotensin II-induced hypertension and associated cardiovascular pathophysiological changes are mediated by cPLA2α activation, most likely through the release of arachidonic acid and generation of eicosanoids with predominant prohypertensive effects and activation of ≥1 signaling molecules, including ERK1/2 and cSrc. © 2015 American Heart Association, Inc.

The interplay between Angiotensin II, TLR4 and hypertension.

PubMed

Biancardi, Vinicia Campana; Bomfim, Gisele Facholi; Reis, Wagner Luis; Al-Gassimi, Sarah; Nunes, Kenia Pedrosa

2017-06-01

Hypertension is a multifactorial disease. Although a number of different underlying mechanisms have been learned from the various experimental models of the disease, hypertension still poses challenges for treatment. Angiotensin II plays an unquestionable role in blood pressure regulation acting through central and peripheral mechanisms. During hypertension, dysregulation of the Renin-Angiotensin System is associated with increased expression of pro-inflammatory cytokines and reactive oxygen species causing kidney damage, endothelial dysfunction, and increase in sympathetic activity, among other damages, eventually leading to decline in organ function. Recent studies have shown that these effects involve both the innate and the adaptive immune response. The contribution of adaptive immune responses involving different lymphocyte populations in various models of hypertension has been extensively studied. However, the involvement of the innate immunity mediating inflammation in hypertension is still not well understood. The innate and adaptive immune systems intimately interact with one another and are essential to an effectively functioning of the immune response; hence, the importance of a better understanding of the underlying mechanisms mediating innate immune system during hypertension. In this review, we aim to discuss mechanisms linking Angiotensin II and the innate immune system, in the pathogenesis of hypertension. The newest research investigating Angiotensin II triggering toll like receptor 4 activation in the kidney, vasculature and central nervous system contributing to hypertension will be discussed. Understanding the role of the innate immune system in the development of hypertension may bring to light new insights necessary to improve hypertension management. Copyright © 2017 Elsevier Ltd. All rights reserved.

UAP56 is an important mediator of Angiotensin II/platelet derived growth factor induced vascular smooth muscle cell DNA synthesis and proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahni, Abha; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555; Wang, Nadan

2013-02-15

Highlights: ► Knockdown of UAP56 inhibits Angiotensin II/PDGF induced vascular smooth muscle cell proliferation. ► UAP56 is a positive regulator of E2F transcriptional activation. ► UAP56 is present in the vessel wall of low flow carotid arteries. -- Abstract: Angiotensin (Ang) II and platelet-derived growth factor (PDGF) are important mediators of pathologic vascular smooth muscle cell (VSMC) proliferation. Identifying downstream mediators of Ang II and PDGF signaling may provide insights for therapies to improve vascular proliferative diseases. We have previously demonstrated that breakpoint cluster region (Bcr) is an important mediator of Ang II/PDGF signaling in VSMC. We have recently reportedmore » that the DExD/H box protein UAP56 is an interacting partner of Bcr in regulating VSMC DNA synthesis. We hypothesized that UAP56 itself is an important regulator of VSMC proliferation. In this report we demonstrate that knockdown of UAP56 inhibits Ang II/PDGF induced VSMC DNA synthesis and proliferation, and inhibits E2F transcriptional activity. In addition, we demonstrate that UAP56 is present in the vessel wall of low-flow carotid arteries. These findings suggest that UAP56 is a regulator of VSMC proliferation and identify UAP56 as a target for preventing vascular proliferative disease.« less

Enkephalin inhibition of angiotensin-stimulated release of oxytocin and vasopressin

NASA Technical Reports Server (NTRS)

Keil, L. C.; Chee, O.; Rosella-Dampman, L. M.; Emmert, S.; Summy-Long, J. Y.

1984-01-01

The effect of intracerebroventricular (ICV) pretreatment with 100 ng/5 microliter leucine(5)-enkephalin (LE) on the increase in plasma oxytocin (OT) and vasopressin (VP) caused by ICV injection of 10, 50, or 100 ng/5 microliter of angiotensin II (AII) is investigated experimentally in conscious adult male Sprague-Dawley rats; the effects of water-deprivation dehydration and lactation/suckling (in female rats) are also studied. An OT radioimmunoassay (RIA) with a sensitivity of 800 fg/ml (described in detail) and the VP RIA technique of Keil and Severs (1977) are employed. Administration of AII or dehydration for 48 or 72 h cause a significant increase in OT and VP without affecting the ratio, while lactation and suckling increase OT only. LE pretreatment inhibits significantly but does not suppress the AII-stimulated OT-VP response.

Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade.

PubMed

Tsukuda, Kana; Mogi, Masaki; Iwanami, Jun; Kanno, Harumi; Nakaoka, Hirotomo; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Higaki, Akinori; Yamauchi, Toshifumi; Min, Li-Juan; Horiuchi, Masatsugu

2016-01-01

Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named 'beige' or 'brite' adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders.

Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure.

PubMed

Takane, Koki; Hasegawa, Yu; Lin, Bowen; Koibuchi, Nobutaka; Cao, Cheng; Yokoo, Takashi; Kim-Mitsuyama, Shokei

2017-04-20

The significance of brain angiotensin II in Alzheimer disease (AD) is unclear. To examine the role of brain angiotensin II in AD, intracerebroventricular angiotensin II infusion was performed on 5XFAD mice, a mouse model of AD, and wild-type mice, and the detrimental effects of brain angiotensin II was compared between the 2 strains of mice. Intracerebroventricular angiotensin II infusion significantly impaired cognitive function in 5XFAD mice but not in wild-type mice. This vulnerability of 5XFAD mice to brain angiotensin II was associated with enhancement of hippocampal inflammation and oxidative stress and with increased cerebrovascular amyloid β deposition. We also compared the effect of brain angiotensin II on the heart and skeletal muscle between the 2 strains because AD is associated with heart failure and sarcopenia. We found that cardiac compensatory response of 5XFAD mice to brain angiotensin II-induced hypertension was less than that of wild-type mice. Brain angiotensin II caused skeletal muscle atrophy and injury in 5XFAD mice more than in wild-type mice. Brain angiotensin II seems to be involved in cognitive impairment and brain injury in AD, which is associated with oxidative stress, inflammation, and cerebral amyloid angiopathy. Further, brain angiotensin II may participate in cardiac disease and sarcopenia observed in AD. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Angiotensin II-AT1-receptor signaling is necessary for cyclooxygenase-2-dependent postnatal nephron generation.

PubMed

Frölich, Stefanie; Slattery, Patrick; Thomas, Dominique; Goren, Itamar; Ferreiros, Nerea; Jensen, Boye L; Nüsing, Rolf M

2017-04-01

Deletion of cyclooxygenase-2 (COX-2) causes impairment of postnatal kidney development. Here we tested whether the renin angiotensin system contributes to COX-2-dependent nephrogenesis in mice after birth and whether a rescue of impaired renal development and function in COX-2 -/- mice was achievable. Plasma renin concentration in mouse pups showed a birth peak and a second peak around day P8 during the first 10 days post birth. Administration of the angiotensin II receptor AT1 antagonist telmisartan from day P1 to P3 did not result in cortical damage. However, telmisartan treatment from day P3 to P8, the critical time frame of renal COX-2 expression, led to hypoplastic glomeruli, a thinned subcapsular cortex and maturational arrest of superficial glomeruli quite similar to that observed in COX-2 -/- mice. In contrast, AT2 receptor antagonist PD123319 was without any effect on renal development. Inhibition of the renin angiotensin system by aliskiren and enalapril caused similar glomerular defects as telmisartan. Administration of the AT1 receptor agonist L162313 to COX-2 -/- pups improved kidney growth, ameliorated renal defects, but had no beneficial effect on reduced cortical mass. L162313 rescued impaired renal function by reducing serum urea and creatinine and mitigated pathologic albumin excretion. Moreover, glomerulosclerosis in the kidneys of COX-2 -/- mice was reduced. Thus, angiotensin II-AT1-receptor signaling is necessary for COX-2-dependent normal postnatal nephrogenesis and maturation. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway.

PubMed

van der Lubbe, Nils; Lim, Christina H; Meima, Marcel E; van Veghel, Richard; Rosenbaek, Lena Lindtoft; Mutig, Kerim; Danser, Alexander H J; Fenton, Robert A; Zietse, Robert; Hoorn, Ewout J

2012-06-01

We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin-angiotensin-aldosterone system.

Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats.

PubMed

Li, Jing; He, Jiaojun; Du, Yuanhao; Cui, Jingjun; Ma, Ying; Zhang, Xuezhu

2014-11-11

To investigate the effects and potential mechanism of electroacupuncture intervention on expressions of Angiotensin II and its receptors-mediated signaling pathway in experimentally induced cerebral ischemia. Totally 126 male Wistar rats were randomly divided into control group, model group and EA group. The latter two were further divided into ten subgroups (n = 6) following Middle Cerebral Artery Occlusion (MCAO). Changes in regional cerebral blood flow (rCBF) and expressions of Angiotensin II and its receptors (AT1R, AT2R), as well as effector proteins in phosphatidyl inositol signal pathway were monitored before and at different times after MCAO. MCAO-induced decline of ipsilateral rCBF was partially suppressed by electroacupuncture, and contralateral blood flow was also superior to that of model group. Angiotensin II level was remarkably elevated immediately after MCAO, while electroacupuncture group exhibited significantly lower levels at 1 to 3 h and the value was significantly increased thereafter. The enhanced expression of AT1R was partially inhibited by electroacupuncture, while increased AT2R level was further induced. Electroacupuncture stimulation attenuated and postponed the upregulated-expressions of Gq and CaM these upregulations. ELISA results showed sharply increased expressions of DAG and IP3, which were remarkably neutralized by electroacupuncture. MCAO induced significant increases in expression of Angiotensin II and its receptor-mediated signal pathway. These enhanced expressions were significantly attenuated by electroacupuncture intervention, followed by reduced vasoconstriction and improved blood supply in ischemic region, and ultimately conferred beneficial effects on cerebral ischemia.

Substance P increases Sympathetic Activity during Combined Angiotensin Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition

PubMed Central

Devin, Jessica K.; Pretorius, Mias; Nian, Hui; Yu, Chang; Billings, Frederic T.; Brown, Nancy J.

2014-01-01

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce post-prandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme. During angiotensin-converting enzyme inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, while bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when angiotensin-converting enzyme is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg p.o. or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat, however, substance P increased heart rate and vascular release of norepinephrine during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. PMID:24516103

Inhibition of angiotensin-converting enzyme increases oestradiol production in ewes submitted to oestrous synchronization protocol.

PubMed

Costa, A s; Junior, A S; Viana, G E N; Muratori, M C S; Reis, A M; Costa, A P R

2014-10-01

This study aimed at evaluating the effects of angiotensin-converting enzyme inhibitor (enalapril) and angiotensin II antagonist (valsartan) on the oestradiol and progesterone production in ewes submitted to oestrous synchronization protocol. The animals were weighed and randomly divided into three groups (n = 7). A pre-experiment conducted to verify the effectiveness and toxicity of enalapril (0.5 mg/kg LW) and valsartan (2.2 mg/kg LW) showed that, in the doses used, these drugs were effective in reducing blood pressure without producing toxic effects. In the experiment, all animals were subjected to oestrous synchronization protocol during 12 days. On D10, D11 and D12, animals received saline, enalapril or valsartan (same doses of the pre-experiment), according to the group randomly divided. The hormonal analysis showed an increase in oestradiol on the last day of the protocol (D12) in animals that received enalapril (p < 0.05), but not in other groups, without changing the concentration of progesterone in any of the treatments. It is concluded that valsartan and enalapril are safe and effective subcutaneously for use in sheep and that the angiotensin-converting enzyme (ACE) inhibition with enalapril leads to an increase in oestradiol production near ovulation without changing the concentration of progesterone. This shows that ACE inhibition may be a useful tool in reproductive biotechnologies involving induction and synchronization of oestrus and ovulation in sheep. © 2014 Blackwell Verlag GmbH.

Pharmacological characterization of BR-A-657, a highly potent nonpeptide angiotensin II receptor antagonist.

PubMed

Chi, Yong Ha; Lee, Joo Han; Kim, Je Hak; Tan, Hyun Kwang; Kim, Sang Lin; Lee, Jae Yeol; Rim, Hong-Kun; Paik, Soo Heui; Lee, Kyung-Tae

2013-01-01

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

Differentiation in the angiotensin II receptor 1 blocker class on autonomic function.

PubMed

Krum, H

2001-09-01

Autonomic function is disordered in cardiovascular disease states such as chronic heart failure (CHF) and hypertension. Interactions between the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) may potentially occur at a number of sites. These include central sites (eg, rostral ventrolateral medulla), at the level of baroreflex control, and at the sympathetic prejunctional angiotensin II receptor 1 (AT(1)) receptor, which is facilitatory for norepinephrine release from the sympathetic nerve terminal. Therefore, drugs that block the RAAS may be expected to improve autonomic dysfunction in cardiovascular disease states. In order to test the hypothesis that RAAS inhibition directly reduces SNS activity, a pithed rat model of sympathetic stimulation has been established. In this model, an increase in frequency of stimulation results in a pressor response that is sympathetically mediated and highly reproducible. This pressor response is enhanced in the presence of angiotensin II and is reduced in the presence of nonselective AIIRAs that block both AT(1) and AT(2) receptor subtypes (eg, saralasin). AT(1)-selective antagonists have also been studied in this model, at pharmacologically relevant doses. In one such study, only the AT(1) blocker eprosartan reduced sympathetically stimulated increases in blood pressure, whereas comparable doses of losartan, valsartan, and irbesartan did not. The reason(s) for the differences between eprosartan and other agents of this class on sympathetic modulation are not clear, but may relate to the chemical structure of the drug (a non- biphenyl tetrazole structure that is chemically distinct from the structure of other AIIRAs), receptor binding characteristics (competitive), or unique effects on presynaptic AT(1) receptors.

Brain-mediated dysregulation of the bone marrow activity in angiotensin II-induced hypertension.

PubMed

Jun, Joo Yun; Zubcevic, Jasenka; Qi, Yanfei; Afzal, Aqeela; Carvajal, Jessica Marulanda; Thinschmidt, Jeffrey S; Grant, Maria B; Mocco, J; Raizada, Mohan K

2012-11-01

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in

miR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy.

PubMed

Yang, Yong; Zhou, Yong; Cao, Zheng; Tong, Xin Zhu; Xie, Hua Qiang; Luo, Tao; Hua, Xian Ping; Wang, Han Qin

2016-09-01

Cardiac hypertrophy is characterized by maladaptive tissue remodeling that may lead to heart failure or sudden death. MicroRNAs (miRs) are negative regulators of angiotensin II and the angiotensin II receptor subtype 1 (AGTR 1 ), which are two components involved in cardiac hypertrophy. In the present study, the interaction between angiotensin II receptor subtype 1 (AGTR 1 ) signaling and miR-155 was investigated. Rat H9C2 (2-1) cardiomyocytes were transfected with miR-155 analogues or inhibitors, then stimulated with angiotensin II to induce cardiac hypertrophy. miR-155 expression was revealed to be altered following transfection with chemically-modified miR-155 analogues and inhibitors in rat cardiomyocytes. In cell cardiac hypertrophy models, the cell surface area, AGTR 1 , atrial natriuretic peptide and myosin heavy chain-β mRNA expression levels were revealed to be lower in cells stimulated with miR-155 analogue-transfected cells treated with angiotensin II compared with cells stimulated with angiotensin alone (P<0.05), as determined using reverse transcription-polymerase chain reaction (PCR), quantitative PCR and western blot analyses. Furthermore, calcineurin mRNA and protein, intracellular free calcium and nuclear factor of activated T-cells-4 proteins were downregulated in miR-155 analogue-transfected cells treated with angiotensin II, as compared with cells stimulated with angiotensin II alone (P<0.05). In conclusion, the current study indicates that miR-155 may improve cardiac hypertrophy by downregulating AGTR 1 and suppressing the calcium signaling pathways activated by AGTR 1 .

Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

PubMed

Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

2016-06-15

Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

Angiotensin II Type 1 Receptor-Associated Protein Regulates Kidney Aging and Lifespan Independent of Angiotensin.

PubMed

Uneda, Kazushi; Wakui, Hiromichi; Maeda, Akinobu; Azushima, Kengo; Kobayashi, Ryu; Haku, Sona; Ohki, Kohji; Haruhara, Kotaro; Kinguchi, Sho; Matsuda, Miyuki; Ohsawa, Masato; Minegishi, Shintaro; Ishigami, Tomoaki; Toya, Yoshiyuki; Atobe, Yoshitoshi; Yamashita, Akio; Umemura, Satoshi; Tamura, Kouichi

2017-07-27

The kidney is easily affected by aging-associated changes, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Particularly, renal tubulointerstitial fibrosis is a final common pathway in most forms of progressive renal disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyperactivation of AT1R signaling, but does not affect physiological AT1R signaling. We hypothesized that ATRAP has a novel functional role in the physiological age-degenerative process, independent of modulation of AT1R signaling. ATRAP-knockout mice were used to study the functional involvement of ATRAP in the aging. ATRAP-knockout mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in ATRAP-knockout mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) life span is 18.4% shorter (median life span, 100.4 versus 123.1 weeks). As a key mechanism, age-related pathological changes in the kidney of ATRAP-knockout mice correlated with decreased expression of the prosurvival gene, Sirtuin1 . On the other hand, chronic angiotensin II infusion did not affect renal sirtuin1 expression in wild-type mice. These results indicate that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

CHBPR: ANGIOTENSIN II, INDEPENDENT OF PLASMA RENIN ACTIVITY, CONTRIBUTES TO THE HYPERTENSION OF AUTONOMIC FAILURE

PubMed Central

Arnold, Amy C.; Okamoto, Luis E.; Gamboa, Alfredo; Shibao, Cyndya; Raj, Satish R.; Robertson, David; Biaggioni, Italo

2013-01-01

At least half of primary autonomic failure patients exhibit supine hypertension, despite profound impairments in sympathetic activity. While the mechanisms underlying this hypertension are unknown, plasma renin activity is often undetectable suggesting renin-angiotensin pathways are not involved. However, because aldosterone levels are preserved, we tested the hypothesis that angiotensin II is intact and contributes to the hypertension of autonomic failure. Indeed, circulating angiotensin II was paradoxically increased in hypertensive autonomic failure patients (52±5 pg/ml, n=11) compared to matched healthy controls (27±4 pg/ml, n=10; p=0.002), despite similarly low renin activity (0.19±0.06 versus 0.34±0.13 ng/ml/hr, respectively; p=0.449). To determine the contribution of angiotensin II to supine hypertension in these patients, we administered the AT1 receptor blocker losartan (50 mg) at bedtime in a randomized, double-blind, placebo-controlled study (n=11). Losartan maximally reduced systolic blood pressure by 32±11 mmHg at 6 hours after administration (p<0.05), decreased nocturnal urinary sodium excretion (p=0.0461), and did not worsen morning orthostatic tolerance. In contrast, there was no effect of the captopril on supine blood pressure in a subset of these patients. These findings suggest that angiotensin II formation in autonomic failure is independent of plasma renin activity, and perhaps angiotensin converting enzyme. Furthermore, these studies suggest that elevations in angiotensin II contribute to the hypertension of autonomic failure, and provide rationale for the use of AT1 receptor blockers for treatment of these patients. PMID:23266540

6β-HYDROXYTESTOSTERONE, A CYTOCHROME P450 1B1-TESTOSTERONE-METABOLITE, MEDIATES ANGIOTENSIN II-INDUCED RENAL DYSFUNCTION IN MALE MICE

PubMed Central

Pingili, Ajeeth K.; Thirunavukkarasu, Shyamala; Kara, Mehmet; Brand, David; Katsurada, Akemi; Majid, Dewan S. A.; Navar, L. Gabriel; Gonzalez, Frank J.; Malik, Kafait U.

2016-01-01

6β-hydroxytestosterone, a cytochrome P450 1B1-derived metabolite of testosterone, contributes to the development of angiotensin II-induced hypertension and associated cardiovascular pathophysiology. In view of the critical role of angiotensin II in the maintenance of renal homeostasis, development of hypertension and end organ damage, this study was conducted to determine the contribution of 6β-hydroxytestosterone to angiotensin II actions on water consumption and renal function in male Cyp1b1+/+ and Cyp1b1−/− mice. Castration of Cyp1b1+/+ mice or Cyp1b1−/− gene disruption minimized the angiotensin II-induced increase in water consumption, urine output, proteinuria, and sodium excretion and decreases in urine osmolality. 6β-hydroxytestosterone did not alter angiotensin II-induced increases in water intake, urine output, proteinuria, and sodium excretion or decreases in osmolality in Cyp1b1+/+ mice, but restored these effects of angiotensin II in Cyp1b1−/− or castrated mice Cyp1b1+/+ mice. Cyp1b1 gene disruption or castration prevented angiotensin II-induced renal fibrosis, oxidative stress, inflammation, urinary excretion of angiotensinogen, expression of angiotensin II type 1 receptor, and angiotensin converting enzyme. 6β-hydroxytestosterone did not alter angiotensin II-induced renal fibrosis, inflammation, oxidative stress, urinary excretion angiotensinogen, expression of angiotensin II type 1 receptor, or angiotensin converting enzyme in Cyp1b1+/+ mice; however, in Cyp1b1−/− or castrated mice Cyp1b1+/+ mice, it restored these effects of angiotensin II. These data indicate that 6β-hydroxytestosterone contributes to increased thirst, impairment of renal function, and end organ injury associated with angiotensin II-induced hypertension in male mice and that cytochrome P450 1B1 could serve as a novel target for treating renal disease and hypertension in males. PMID:26928804

Angiotensin II type 1 receptor-associated protein regulates carotid intimal hyperplasia through controlling apoptosis of vascular smooth muscle cells.

PubMed

Yue, Yongqiang; Ma, Ke; Li, Zhen; Wang, Zhonggao

2018-01-08

Intimal hyperplasia is the main cause of restenosis after carotid artery injury, and the underlying mechanism involves the proliferation and migration of vascular smooth muscle cells (VSMCs). Angiotensin II Type 1 Receptor-Associated Protein (ATRAP) has been reported to withstand intimal hyperplasia by inhibiting VSMCs proliferation and migration; however, whether the beneficial effect of ATRAP associates with VSMCs apoptosis remains unclarified. We demonstrated that the adenoviral-mediated overexpression of ATRAP induced VSMC apoptosis, alleviating the balloon injury-induced neointima formation in rats. Under the condition of Angiotensin-II stimulation, ATRAP overexpression induced the apoptosis of rat VSMCs by depressing the PI3K-Akt signaling; whereas up-regulation of Akt by PTEN inhibitor abolished the apoptotic death. Thus, ATRAP regulates carotid intimal hyperplasia through controlling the PI3K-Akt signal-mediated VSMCs apoptosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension.

PubMed

Rincón, J; Correia, D; Arcaya, J L; Finol, E; Fernández, A; Pérez, M; Yaguas, K; Talavera, E; Chávez, M; Summer, R; Romero, F

2015-03-01

Activation of the renin-angiotensin system (RAS), renal oxidative stress and inflammation are constantly present in experimental hypertension. Nitric oxide (NO) inhibition with N(w)-nitro-L-arginine methyl ester (L-NAME) has previously been reported to produce hypertension, increased expression of Angiotensin II (Ang II) and renal dysfunction. The use of Losartan, an Ang II type 1 receptor (AT1R) antagonist has proven to be effective reducing hypertension and renal damage; however, the mechanism by which AT1R blockade reduced kidney injury and normalizes blood pressure in this experimental model is still complete unknown. The current study was designed to test the hypothesis that AT1R activation promotes renal NAD(P)H oxidase up-regulation, oxidative stress and cytokine production during L-NAME induced-hypertension. Male Sprague-Dawley rats were distributed in three groups: L-NAME, receiving 70 mg/100ml of L-NAME, L-NAME+Los, receiving 70 mg/100ml of L-NAME and 40 mg/kg/day of Losartan; and Controls, receiving water instead of L-NAME or L-NAME and Losartan. After two weeks, L-NAME induced high blood pressure, renal overexpression of AT1R, NAD(P)H oxidase sub-units gp91, p22 and p47, increased levels of oxidative stress, interleukin-6 (IL-6) and interleukin-17 (IL-17). Also, we found increased renal accumulation of lymphocytes and macrophages. Losartan treatment abolished the renal expression of gp91, p22, p47, oxidative stress and reduced NF-κB activation and IL-6 expression. These findings indicate that NO induced-hypertension is associated with up-regulation of NADPH oxidase, oxidative stress production and overexpression of key inflammatory mediators. These events are associated with up-regulation of AT1R, as evidenced by their reversal with AT1R blocker treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

Angiotensin II promotes the proliferation of activated pancreatic stellate cells by Smad7 induction through a protein kinase C pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hama, Kouji; Ohnishi, Hirohide; Aoki, Hiroyoshi

2006-02-17

Activated pancreatic stellate cells (PSCs) play major roles in promoting pancreatic fibrosis. We previously reported that angiotensin II (Ang II) enhances activated PSC proliferation through EGF receptor transactivation. In the present study, we elucidated a novel intracellular mechanism by which Ang II stimulates cellular proliferation. TGF-{beta}{sub 1} inhibits activated PSC proliferation via a Smad3 and Smad4-dependent pathway in an autocrine manner. We demonstrated that Ang II inhibited TGF-{beta}{sub 1}-induced nuclear accumulation of Smad3 and Smad4. Furthermore, Ang II rapidly induced inhibitory Smad7 mRNA expression. Adenovirus-mediated Smad7 overexpression inhibited TGF-{beta}{sub 1}-induced nuclear accumulation of Smad3 and Smad4, and potentiated activated PSCmore » proliferation. PKC inhibitor Go6983 blocked the induction of Smad7 mRNA expression by Ang II. In addition, 12-O-tetradecanoyl-phorbol 13-acetate, a PKC activator, increased Smad7 mRNA expression. These results suggest that Ang II enhances activated PSC proliferation by blocking autocrine TGF-{beta}{sub 1}-mediated growth inhibition by inducing Smad7 expression via a PKC-dependent pathway.« less

The Arrestin-selective Angiotensin AT1 Receptor Agonist [Sar1,Ile4,Ile8]-AngII Negatively Regulates Bradykinin B2 Receptor Signaling via AT1-B2 Receptor Heterodimers*

PubMed Central

Wilson, Parker C.; Lee, Mi-Hye; Appleton, Kathryn M.; El-Shewy, Hesham M.; Morinelli, Thomas A.; Peterson, Yuri K.; Luttrell, Louis M.; Jaffa, Ayad A.

2013-01-01

The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin-angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar1,Ile4,Ile8]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar1,Ile4, Ile8]-AngII require the AT1 receptor and result from arrestin-dependent co-internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar1,Ile4,Ile8]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar1,Ile4,Ile8]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar1,Ile4,Ile8]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar1,Ile4,Ile8]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic actions. PMID:23661707

The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers.

PubMed

Wilson, Parker C; Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M; Morinelli, Thomas A; Peterson, Yuri K; Luttrell, Louis M; Jaffa, Ayad A

2013-06-28

The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin-angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar(1),Ile(4),Ile(8)]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar(1),Ile(4), Ile(8)]-AngII require the AT1 receptor and result from arrestin-dependent co-internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar(1),Ile(4),Ile(8)]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar(1),Ile(4),Ile(8)]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar(1),Ile(4),Ile(8)]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar(1),Ile(4),Ile(8)]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic

Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes.

PubMed

Velez, Juan Carlos Q; Bland, Alison M; Arthur, John M; Raymond, John R; Janech, Michael G

2007-07-01

Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 microM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 microM ANG I primarily formed ANG-(1-9) and ANG-(1-7). In contrast, MES incubated with ANG I primarily generated ANG II. In POD, ANG-(1-7) was the predominant product, and its formation was inhibited by a neprilysin inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 microM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to ANG I and ANG-(1-7). This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin system characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which predominantly lead to ANG-(1-7) and ANG-(1-9) formation, as well as ANG II degradation. These findings may reflect a specific role of POD in maintenance of intraglomerular renin-angiotensin system balance.

Role of angiotensin II and angiotensin type-1 receptor in scorpion venom-induced cardiac and aortic tissue inflammation.

PubMed

Sifi, Amina; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

2017-02-01

Scorpion stings are mainly associated with cardiovascular disturbances that may be the cause of death. In this study, the involvement of angiotensin II (Ang II) in cardiac and aortic inflammatory response was studied. Mice were injected with Androctonus australis hector (Aah) scorpion venom (0.5mg/kg, subcutaneously), in the presence or absence of an angiotensin converting enzyme (ACE) inhibitor, captopril (15mg/kg/day/1day intraperitoneally) or an angiotensin type-1 receptor (AT1R) antagonist, valsartan (15mg/kg/day/15days, orally). In the envenomed group, results revealed severe tissue alterations with a concomitant increase of metabolic enzymes (CK and CK-MB) in sera. An important inflammatory cell (neutrophil and eosinophil) infiltration into the heart and aorta were observed, accompanied by imbalanced redox status (NO, MDA, catalase and GSH) and high cytokine levels (IL-6 and TNF-α) in sera with the expression of MMP-2 and MMP-9 metalloproteinases. However, the blockade of the actions of AngII by the ACE inhibitor or by the AT1R antagonist prevented cardiac and aortic tissue alterations, inflammatory cell infiltration, as well as the oxidative stress generation and cytokine and metalloproteinase expression. These results suggest the involvement of AngII, through its AT1R in the inflammation induced by Aah venom, in the heart and the aorta. Copyright © 2016 Elsevier Inc. All rights reserved.

α2-Macroglobulin Capture Allows Detection of Mast Cell Chymase in Serum and Creates a Circulating Reservoir of Angiotensin II-generating Activity1

PubMed Central

Raymond, Wilfred W.; Su, Sharon; Makarova, Anastasia; Wilson, Todd M.; Carter, Melody C.; Metcalfe, Dean D.; Caughey, George H.

2009-01-01

Human chymase is a highly efficient angiotensin II-generating serine peptidase expressed by the MCTC subset of mast cells. When secreted from degranulating cells, it can interact with a variety of circulating anti-peptidases, but is mostly captured by α2-macroglobulin, which sequesters peptidases in a cage-like structure that precludes interactions with large protein substrates and inhibitors, like serpins. The present work shows that α2-macroglobulin-bound chymase remains accessible to small substrates, including angiotensin I, with activity in serum that is stable with prolonged incubation. We used α2-macroglobulin capture to develop a sensitive, microtiter plate-based assay for serum chymase, assisted by a novel substrate synthesized based on results of combinatorial screening of peptide substrates. The substrate has low background hydrolysis in serum and is chymase-selective, with minimal cleavage by the chymotryptic peptidases cathepsin G and chymotrypsin. The assay detects activity in chymase-spiked serum with a threshold of ~1 pM (30 pg/ml), and reveals native chymase activity in serum of most subjects with systemic mastocytosis. α2-Macroglobulin-bound chymase generates angiotensin II in chymase-spiked serum, and appears in native serum as chymostatin-inhibited activity, which can exceed activity of captopril-sensitive angiotensin converting enzyme. These findings suggest that chymase bound to α2-macroglobulin is active, that the circulating complex is an angiotensin-converting enzyme inhibitor-resistant reservoir of angiotensin II-generating activity, and that α2-macroglobulin capture may be exploited in assessing systemic release of secreted peptidases. PMID:19380825

Angiotensin II attenuates NMDA receptor-mediated neuronal cell death and prevents the associated reduction in Bcl-2 expression.

PubMed

Schelman, William R; Andres, Robert; Ferguson, Paul; Orr, Brent; Kang, Evan; Weyhenmeyer, James A

2004-09-10

While angiotensin II (Ang II) plays a major role in the regulation of blood pressure, fluid homeostasis and neuroendocrine function, recent studies have also implicated the peptide hormone in cell growth, differentiation and apoptosis. In support of this, we have previously demonstrated that Ang II attenuates N-methyl-D-aspartate (NMDA) receptor signaling [Molec. Brain Res. 48 (1997) 197]. To further examine the modulatory role of Ang II on NMDA receptor function, we investigated the effect of angiotensin receptor (AT) activation on NMDA-mediated cell death and the accompanying decrease in Bcl-2 expression. The viability of differentiated N1E-115 and NG108-15 neuronal cell lines was reduced following exposure to NMDA in a dose-dependent manner. MTT analysis (mitochondrial integrity) revealed a decrease in cell survival of 49.4+/-12.3% in NG108 cells and 79.9+/-6.8% in N1E cells following treatment with 10 mM NMDA for 20 h. Cytotoxicity in N1E cells was inhibited by the noncompetitive NMDA receptor antagonist, MK-801. Further, NMDA receptor-mediated cell death in NG108 cells was attenuated by treatment with Ang II. The Ang II effect was inhibited by both AT1 and AT2 receptor antagonists, losartan and PD123319, respectively, suggesting that both receptor subtypes may play a role in the survival effect of Ang II. Since it has been shown that activation of NMDA receptors alters the expression of Bcl-2 family proteins, Western blot analysis was performed in N1E cells to determine whether Ang II alters the NMDA-induced changes in Bcl-2 expression. A concentration-dependent decrease of intracellular Bcl-2 protein levels was observed following treatment with NMDA, and this reduction was inhibited by MK801. Addition of Ang II suppressed the NMDA receptor-mediated reduction in Bcl-2. The Ang II effect on NMDA-mediated changes in Bcl-2 levels was blocked by PD123319, but was not significantly changed by losartan, suggesting AT2 receptor specificity. Taken together, these

Progression is caused by angiotensin II-dependent persistent podocyte loss from destabilized glomeruli

PubMed Central

Fukuda, Akihiro; Wickman, Larysa T.; Venkatareddy, Madhusudan; Sato, Yuji; Chowdhury, Mahboob; Wang, Su Q; Shedden, Kerby; Dysko, Robert; Wiggins, Jocelyn E.; Wiggins, Roger C.

2013-01-01

Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to End Stage Kidney Disease (ESKD). We therefore tested the hypothesis that progression to ESKD can be caused by persistent podocyte loss using the human diphtheria toxin transgenic rat model. After initial podocyte injury causing >30% loss of podocytes glomeruli became destabilized, resulting in continuous podocyte loss over time until global podocyte depletion (ESKD) occured. Similar patterns of podocyte depletion were observed in the puromycin aminonucleoside and 5/6 nephrectomy rat models of progression. Angiotensin II blockade prevented continuous podocyte loss and progression (restabilized glomeruli). Discontinuing angiotensin II blockade resulted in recurrent glomerular destabilization, podocyte loss and progression. Reduction in blood pressure alone did not reduce proteinuria or prevent podocyte loss from destabilized glomeruli. The protective effect of angiotensin II blockade could be entirely accounted for by reduction in podocyte loss. These data demonstrate that an initiating event that results in a critical degree of podocyte depletion can destabilize glomeruli by setting in train a superimposed angiotensin II-dependent podocyte loss cycle that accelerates the progression process and results in global podocyte depletion and progression to ESKD. These events can be monitored non-invasively through urine mRNA assays. PMID:21937979

Increased Sensitivity to Angiotensin II is Present Postpartum in Women with History of Hypertensive Pregnancy

PubMed Central

Saxena, Aditi R.; Karumanchi, S. Ananth; Brown, Nancy J.; Royle, Caroline M.; McElrath, Thomas F.; Seely, Ellen W.

2010-01-01

Pregnancies complicated by new onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear if this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high and low sodium balance. Ten women had history of hypertensive pregnancy (five with preeclampsia; five with transient hypertension of pregnancy) and 15 women had history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone and soluble fms-like tyrosine kinase 1 (sFlt-1) levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 vs. 104 mmHg and 73 vs. 65 mmHg, respectively, p<0.05). Women with history of hypertensive pregnancy had pressor response to salt loading, demonstrated by increase in systolic blood pressure on high salt diet. They also had greater systolic pressor response (10 vs. 2 mmHg, p=0.03), greater increase in aldosterone (56.8 vs. 30.8 ng/dL, p=0.03) and increase in sFlt-1 levels (11.0 vs. -18.9 pg/mL, p=0.02) after infusion of angiotensin II in low sodium balance, compared with controls. Thus, women with history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal and sFlt-1 responses to infused angiotensin II in low sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women. PMID:20308605

Azilsartan Medoxomil, an Angiotensin II Receptor Antagonist for the Treatment of Hypertension.

PubMed

Hjermitslev, Marie; Grimm, Daniela G; Wehland, Markus; Simonsen, Ulf; Krüger, Marcus

2017-10-01

Azilsartan (AZL) medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin II receptor blockers (ARBs) that have been on the market for a longer period. AZL antagonizes the AT 1 receptor for angiotensin II (ANG II), whereas angiotensin-converting enzyme inhibitors block the conversion of angiotensin I to ANG II, but not alternative routes of formation of ANG II. The bioavailability of AZL is about 60% and it has a t max of 1.5-3 hr and a half-life of approximately 11 hr. With its IC 50 of 7.4 nM after 5 hr of drug washout in radioligand assays, AZL has a tighter and longer-lasting binding to the AT 1 receptor by several orders of magnitude than other ARBs, which might lead to a more effective reduction in BP. Clinical studies have revealed that AZL doses of 40 and 80 mg/day reduce BP significantly better than maximal clinical doses of valsartan or olmesartan, while being well tolerated and exhibiting a spectrum of adverse effects comparable to those of other ARBs. These properties of AZL might lower the risk of cardiovascular disease and thereby reduce mortality rates. However, the existing mortality studies have not found this correlation, which should be further investigated. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

19-Hydroxyeicosatetraenoic acid and isoniazid protect against angiotensin II-induced cardiac hypertrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elkhatali, Samya; El-Sherbeni, Ahmed A.; Elshenawy, Osama H.

We have recently demonstrated that 19-hydroxyeicosatetraenoic acid (19-HETE) is the major subterminal-HETE formed in the heart tissue, and its formation was decreased during cardiac hypertrophy. In the current study, we examined whether 19-HETE confers cardioprotection against angiotensin II (Ang II)-induced cardiac hypertrophy. The effect of Ang II, with and without 19-HETE (20 μM), on the development of cellular hypertrophy in cardiomyocyte RL-14 cells was assessed by real-time PCR. Also, cardiac hypertrophy was induced in Sprague–Dawley rats by Ang II, and the effect of increasing 19-HETE by isoniazid (INH; 200 mg/kg/day) was assessed by heart weight and echocardiography. Also, alterations inmore » cardiac cytochrome P450 (CYP) and their associated arachidonic acid (AA) metabolites were determined by real-time PCR, Western blotting and liquid-chromatography–mass-spectrometry. Our results demonstrated that 19-HETE conferred a cardioprotective effect against Ang II-induced cellular hypertrophy in vitro, as indicated by the significant reduction in β/α-myosin heavy chain ratio. In vivo, INH improved heart dimensions, and reversed the increase in heart weight to tibia length ratio caused by Ang II. We found a significant increase in cardiac 19-HETE, as well as a significant reduction in AA and its metabolite, 20-HETE. In conclusion, 19-HETE, incubated with cardiomyocytes in vitro or induced in the heart by INH in vivo, provides cardioprotection against Ang II-induced hypertrophy. This further confirms the role of CYP, and their associated AA metabolites in the development of cardiac hypertrophy. - Highlights: • We found 19-hydroxy arachidonic acid to protect cardiomyocytes from hypertrophy. • We validated the use of isoniazid as a cardiac 19-hydroxy arachidonic acid inducer. • We found isoniazid to increase protective and inhibit toxic eicosanoides. • We found isoniazid to protect against angiotensin-induced cardiac hypertrophy. • This will help

Treatment with salvianolic acid B restores endothelial function in angiotensin II-induced hypertensive mice.

PubMed

Ling, Wei Chih; Liu, Jian; Lau, Chi Wai; Murugan, Dharmani Devi; Mustafa, Mohd Rais; Huang, Yu

2017-07-15

Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25mg/kg/day) was administered via oral gavage for 11days to Ang II (1.2mg/kg/day)-infused C57BL/6J mice (8-10weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT 1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1-10nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT 1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11days reverses the impaired endothelial function and with a marked inhibition of AT 1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound. Copyright © 2017 Elsevier Inc. All rights reserved.

Angiotensin II stimulates calcium-dependent activation of c-Jun N-terminal kinase.

PubMed Central

Zohn, I E; Yu, H; Li, X; Cox, A D; Earp, H S

1995-01-01

In GN4 rat liver epithelial cells, angiotensin II (Ang II) and other agonists which activate phospholipase C stimulate tyrosine kinase activity in a calcium-dependent, protein kinase C (PKC)-independent manner. Since Ang II also produces a proliferative response in these cells, we investigated downstream signaling elements traditionally linked to growth control by tyrosine kinases. First, Ang II, like epidermal growth factor (EGF), stimulated AP-1 binding activity in a PKC-independent manner. Because increases in AP-1 can reflect induction of c-Jun and c-Fos, we examined the activity of the mitogen-activated protein (MAP) kinase family members Erk-1 and -2 and the c-Jun N-terminal kinase (JNK), which are known to influence c-Jun and c-Fos transcription. Ang II stimulated MAP kinase (MAPK) activity but only approximately 50% as effectively as EGF; again, these effects were independent of PKC. Ang II also produced a 50- to 200-fold activation of JNK in a PKC-independent manner. Unlike its smaller effect on MAPK, Ang II was approximately four- to sixfold more potent in activating JNK than EGF was. Although others had reported a lack of calcium ionophore-stimulated JNK activity in lymphocytes and several other cell lines, we examined the role of calcium in GN4 cells. The following results suggest that JNK activation in rat liver epithelial cells is at least partially Ca(2+) dependent: (i) norepinephrine and vasopressin hormones that increase inositol 1,4,5-triphosphate stimulated JNK; (ii) both thapsigargin, a compound that produces an intracellular Ca(2+) signal, and Ca(2+) ionophores stimulated a dramatic increase in JNK activity (up to 200-fold); (iii) extracellular Ca(2+) chelation with ethylene glycol tetraacetic acid (EGTA) inhibited JNK activation by ionophore and intracellular chelation with 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl-ester (BAPTA-AM) partially inhibited JNK activation by Ang II or thapsigargin; and (iv) JNK

Dual Angiotensin Receptor and Neprilysin Inhibition with Sacubitril/Valsartan in Chronic Systolic Heart Failure: Understanding the New PARADIGM.

PubMed

Lillyblad, Matthew P

2015-11-01

To evaluate the clinical role of sacubitril/valsartan, a novel angiotensin-neprilysin inhibitor, for the treatment of chronic heart failure with a reduced ejection fraction (HFrEF). A search of PubMed was conducted using a combination of the search terms sacubitril, valsartan, LCZ696, neprilysin inhibition, natriuretic peptide system, renin-angiotensin system, and heart failure with reduced ejection fraction. Bibliographies of all retrieved articles were reviewed for relevant literature. All references included were published between 1980 and May 2015. All studies and review articles that contained data describing the use of sacubitril/valsartan in HFrEF were reviewed. HFrEF remains a disease of high morbidity and mortality. Natriuretic peptide (NP) augmentation has emerged as a most promising neurohormonal target in HFrEF. NPs provide vasodilatory, natriuretic, diuretic, and antiproliferative actions to help support the failing heart. Neprilysin, a neutral endopeptidase, is a primary pathway for NP metabolism. Combined inhibition of the renin angiotensin aldosterone system and neprilysin augments the beneficial natriuretic peptide pathway while providing direct antagonism to increases in angiotensin II. In the landmark PARADIGM HF trial, the neprilysin inhibitor sacubitril added to valsartan significantly improved morbidity and mortality over enalapril, a standard of care in HFrEF. Application of these results to clinical practice requires careful considerations of trial design, study patient population, and clinical monitoring. Sacubitril/valsartan significantly improved morbidity and mortality in patients with chronic HFrEF but will require careful application to "real-world" populations of HFrEF. © The Author(s) 2015.

Common genetic variations of the renin-angiotensin-aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension.

PubMed

Hannila-Handelberg, Tuula; Kontula, Kimmo K; Paukku, Kirsi; Lehtonen, Jukka Y; Virtamo, Jarmo; Tikkanen, Ilkka; Hiltunen, Timo P

2010-04-01

In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients. A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n = 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study. Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P = 0.02) and after 60 min of captopril administration (P = 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P = 0.007) as well as aldosterone/renin ratio (P = 0.04) were significantly higher in the CC genotype (n = 13) than in the AA genotype (n = 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele. The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.

Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma

PubMed Central

Arrieta, O; Guevara, P; Escobar, E; García-Navarrete, R; Pineda, B; Sotelo, J

2005-01-01

Angiotensin II (Ang II) is a main effector peptide in the renin–angiotensin system and participates in the regulation of vascular tone. It also has a role in the expression of growth factors that induce neovascularisation which is closely associated to the growth of malignant gliomas. We have shown that the selective blockage of the AT1 receptor of angiotensin inhibites tumour growth, cell proliferation and angiogenesis of C6 rat glioma. The aim of this study was to study the effects of the blockage of AT1 receptor on the synthesis of growth factors, and in the genesis of apoptosis in cultured C6 glioma cells and in rats with C6 glioma. Administration of losartan at doses of 40 or 80 mg kg−1 to rats with C6 glioma significantly decreased tumoral volume and production of platelet-derived growth factor, vascular endothelial growth factor and basic fibroblast growth factor. It also induced apoptosis in a dose-dependent manner. Administration of Ang II increased cell proliferation of cultured C6 cells which decreased by the administration of losartan. Our results suggest that the selective blockage of AT1 diminishes tumoral growth through inhibition of growth factors and promotion of apoptosis. PMID:15785746

Chronic production of angiotensin IV in the brain leads to hypertension that is reversible with an angiotensin II AT1 receptor antagonist.

PubMed

Lochard, Nadheige; Thibault, Gaétan; Silversides, David W; Touyz, Rhian M; Reudelhuber, Timothy L

2004-06-11

Angiotensin IV (Ang IV) is a metabolite of the potent vasoconstrictor angiotensin II (Ang II). Because specific binding sites for this peptide have been reported in numerous tissues including the brain, it has been suggested that a specific Ang IV receptor (AT4) might exist. Bolus injection of Ang IV in brain ventricles has been implicated in learning, memory, and localized vasodilatation. However, the functions of Ang IV in a physiological context are still unknown. In this study, we generated a transgenic (TG) mouse model that chronically releases Ang IV peptide specifically in the brain. TG mice were found to be hypertensive by the tail-cuff method as compared with control littermates. Treatment with the angiotensin-converting enzyme inhibitor captopril had no effect on blood pressure, but surprisingly treatment with the Ang II AT1 receptor antagonist candesartan normalized the blood pressure despite the fact that the levels of Ang IV in the brains of TG mice were only 4-fold elevated over the normal endogenous level of Ang peptides. Calcium mobilization assays performed on cultured CHO cells chronically transfected with the AT1 receptor confirm that low-dose Ang IV can mobilize calcium via the AT1 receptor only in the presence of Ang II, consistent with an allosteric mechanism. These results suggest that chronic elevation of Ang IV in the brain can induce hypertension that can be treated with angiotensin II AT1 receptor antagonists.

The Divergent Cardiovascular Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Adult Patients With Type 2 Diabetes Mellitus.

PubMed

Strauss, Martin H; Hall, Alistair S

2018-04-01

The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin-converting enzyme inhibitors (ACEi's) suppress angiotensin II (ANG II) concentrations, whereas angiotensin II type 1 (AT 1 ) receptor blockers (ARBs) block the binding of ANG II to AT 1 receptors. ACEi's and ARBs are both effective antihypertensive agents and produce similar risk reductions for stroke, a blood pressure-dependent phenomenon. ACEi's also reduce the risk for myocardial infarction (MI) and all-cause mortality in high-risk hypertensive patients as well as in people with diabetes, vascular disease and congestive heart failure. ARBs, in contrast, do not reduce the risk for MI or death in randomized clinical trials when assessed vs. placebo. Systematic reviews of ARBs that include meta-analyses or metaregression analyses confirm that ARBs lack the cardiovascular-protective effects of ACEi's. Practice guidelines, especially those for high-risk patients, such as those with diabetes mellitus, should reflect the evidence that ACEi's and ARBs have divergent cardiovascular effects: ACEi's reduce mortality, whereas ARBs do not. ACEi's should remain the preferred RAAS inhibitor for patients at high risk. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

The role of mAKAPβ in the process of cardiomyocyte hypertrophy induced by angiotensin II

PubMed Central

GUO, HUIXIN; LIU, BAOXIN; HOU, LEI; THE, ERLINDA; LI, GANG; WANG, DONGZHI; JIE, QIQIANG; CHE, WENLIANG; WEI, YIDONG

2015-01-01

Angiotensin II (AngII) is the central product of the renin-angiotensin system (RAS) and this octapeptide contributes to the pathophysiology of cardiac hypertrophy and remodeling. mAKAPβ is an A-kinase anchoring protein (AKAP) that has the function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. In this study, we aimed to investigate the role of mAKAPβ in AngII-induced cardiomyocyte hypertrophy and the possible mechanisms involved. Cultured cardiomyocytes from neonatal rats were treated with AngII. Subsequently, the morphology of the cardiomyocytes was observed and the expression of mAKAPβ and cardiomyocyte hypertrophic markers was measured. mAKAPβ-shRNA was constructed for RNA interference; the expression of mAKAPβ and hypertrophic markers, the cell surface area and the [3H]Leucine incorporation rate in the AngII-treated rat cardiomyocytes were detected following RNA interference. Simultaneously, changes in the expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK)2 in the cardiomyocytes were assessed. The cell size of the AngII-treated cardiaomyocytes was significantly larger than that of the untreated cardiomyocytes. The expression of hypertrophic markers and p-ERK2, the cell surface area and the [3H]Leucine incorporation rate were all significantly increased in the AngII-treated cells. However, the expression of mAKAPβ remained unaltered in this process. RNA interference simultaneously inhibited the protein expression of mAKAPβ and p-ERK2, and the hypertrophy of the cardiomyocytes induced by AngII was attenuated. These results demonstrate that AngII induces hypertrophy in cardiomyocytes, and mAKAPβ is possibly involved in this process. The effects of mAKAPβ on AngII-induced cardiomyocyte hypertrophy may be associated with p-ERK2 expression. PMID:25739102

Mechanism of high glucose induced angiotensin II production in rat vascular smooth muscle cells.

PubMed

Lavrentyev, Eduard N; Estes, Anne M; Malik, Kafait U

2007-08-31

Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (approximately 23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (approximately 4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymase-dependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG.

Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II.

PubMed

Doublier, Sophie; Salvidio, Gennaro; Lupia, Enrico; Ruotsalainen, Vesa; Verzola, Daniela; Deferrari, Giacomo; Camussi, Giovanni

2003-04-01

We studied the distribution of nephrin in renal biopsies from 17 patients with diabetes and nephrotic syndrome (7 type 1 and 10 type 2 diabetes), 6 patients with diabetes and microalbuminuria (1 type 1 and 5 type 2 diabetes), and 10 normal subjects. Nephrin expression was semiquantitatively evaluated by measuring immunofluorescence intensity by digital image analysis. We found an extensive reduction of nephrin staining in both type 1 (67 +/- 9%; P < 0.001) and type 2 (65 +/- 10%; P < 0.001) diabetic patients with diabetes and nephrotic syndrome when compared with control subjects. The pattern of staining shifted from punctate/linear distribution to granular. In patients with microalbuminuria, the staining pattern of nephrin also showed granular distribution and reduction intensity of 69% in the patient with type 1 diabetes and of 62 +/- 4% (P < 0.001) in the patients with type 2 diabetes. In vitro studies on human cultured podocytes demonstrated that glycated albumin and angiotensin II reduced nephrin expression. Glycated albumin inhibited nephrin synthesis through the engagement of receptor for advanced glycation end products, whereas angiotensin II acted on cytoskeleton redistribution, inducing the shedding of nephrin. This study indicates that the alteration in nephrin expression is an early event in proteinuric patients with diabetes and suggests that glycated albumin and angiotensin II contribute to nephrin downregulation.

Angiotensin I- and II- and norepinephrine-mediated pressor responses in an ancient holostean fish, the bowfin (Amia calva).

PubMed

Butler, D G; Oudit, G Y; Cadinouche, M Z

1995-06-01

Dorsal aortic blood pressure (PSYS, systolic; PDIAS, diastolic; and PDA, mean) and heart rate (HR) were measured in resting freshwater bowfins (n = 6), Amia calva L., before and after i.v. injections of 50, 100, 200, 500, and 1000 ng.kg-1 of synthetic [Asn1, Val5]-angiotensin II (ANG II). Baseline PSYS, PDIAS, and PDA were 27.7 +/- 2.8, 22.4 +/- 1.8, and 24.5 +/- 2 mm Hg, respectively. Bowfins were only moderately responsive to ANG II in a stepwise manner and the increase in blood pressure became significant only at the two highest doses; lower doses tended only to increase arterial pressure. Pressor responses due to 200 and 500 ng.kg-1 decayed over a greater time period compared with other doses. alpha-Adrenergic blockade abolished 70% of the ANG II-mediated pressor responses. Eel, salmon, and goosefish angiotensin I (ANG I; 500 ng.kg-1) elicited similar vasopressor responses (magnitude and time course) which were eliminated by prior angiotensin converting enzyme inhibition (captopril; 2-10 mg.kg-1). Bullfrog ANG I evoked a pressor effect, only at a higher dose (5000 ng.kg-1). Consecutive norepinephrine (NE) injections (100, 200, 500, and 1000 ng.kg-1) increased PSYS, PDIAS, and PDA in a dose-dependent manner which was dependent on alpha-adrenoceptors since phentolamine (1-3 mg.kg-1) abolished 80% of the pressor action of NE. PSYS was elevated by 100 ng.kg-1 of NE but PDIAS and PDA were significantly increased only at 200 ng.kg-1 ANG II and NE had no measurable chronotropic effect and resting HR (27.2 +/- 0.8 beats.min-1) was unchanged. Captopril and phentolamine treatments produced rapid hypotension and bradycardia (25-30%) which lasted from 15 to 30 and 20 to 40 min, respectively. The rising and decreasing phases of the NE-mediated pressor responses had shorter durations than ANG II effects. Tachyphylaxis occurred with the high doses of ANG II and NE. The data show that in the ancient bowfin, which evidently lacks renal juxtaglomerular cells, the cardiovascular

Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats.

PubMed

Chinnathambi, Vijayakumar; More, Amar S; Hankins, Gary D; Yallampalli, Chandra; Sathishkumar, Kunju

2014-07-01

Pre-eclampsia is a life-threatening pregnancy disorder whose pathogenesis remains unclear. Plasma testosterone levels are elevated in pregnant women with pre-eclampsia and polycystic ovary syndrome, who often develop gestational hypertension. We tested the hypothesis that increased gestational testosterone levels induce hypertension via heightened angiotensin II signaling. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate from Gestational Day 15 to 19 to induce a 2-fold increase in plasma testosterone levels, similar to levels observed in clinical conditions like pre-eclampsia. A subset of rats in these two groups was given losartan, an angiotensin II type 1 receptor antagonist by gavage during the course of testosterone exposure. Blood pressure levels were assessed through a carotid arterial catheter and endothelium-independent vascular reactivity through wire myography. Angiotensin II levels in plasma and angiotensin II type 1 receptor expression in mesenteric arteries were also examined. Blood pressure levels were significantly higher on Gestational Day 20 in testosterone-treated dams than in controls. Treatment with losartan during the course of testosterone exposure significantly attenuated testosterone-induced hypertension. Plasma angiotensin II levels were not significantly different between control and testosterone-treated rats; however, elevated testosterone levels significantly increased angiotensin II type 1 receptor protein levels in the mesenteric arteries. In testosterone-treated rats, mesenteric artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K(+) depolarization and phenylephrine were unaffected. The results demonstrate that elevated testosterone during gestation induces hypertension in pregnant rats via heightened angiotensin II type 1 receptor-mediated signaling, providing a molecular mechanism linking elevated maternal testosterone levels with gestational

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

PubMed Central

Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

2017-01-01

Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition. PMID:28146117

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin.

PubMed

Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

2017-01-31

Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-β, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.

Melatonin attenuates angiotensin II-induced cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway.

PubMed

Su, Hongyan; Li, Jingyuan; Chen, Tongshuai; Li, Na; Xiao, Jie; Wang, Shujian; Guo, Xiaobin; Yang, Yi; Bu, Peili

2016-11-01

Melatonin is well known for its cardioprotective effects; however, whether melatonin exerts therapeutic effects on cardiomyocyte hypertrophy remains to be investigated, as do the mechanisms underlying these effects, if they exist. Cyclophilin A (CyPA) and its corresponding receptor, CD147, which exists in a variety of cells, play crucial roles in modulating reactive oxygen species (ROS) production. In this study, we explored the role of the CyPA/CD147 signaling pathway in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy and the protective effects exerted by melatonin against Ang II-induced injury in cultured H9C2 cells. Cyclosporine A, a specific CyPA/CD147 signaling pathway inhibitor, was used to manipulate CyPA/CD147 activity. H9C2 cells were then subjected to Ang II or CyPA treatment in either the absence or presence of melatonin. Our results indicate that Ang II induces cardiomyocyte hypertrophy through the CyPA/CD147 signaling pathway and promotes ROS production, which can be blocked by melatonin pretreatment in a concentration-dependent manner, in cultured H9C2 cells and that CyPA/CD147 signaling pathway inhibition protects against Ang II-induced cardiomyocyte hypertrophy. The protective effects of melatonin against Ang II-induced cardiomyocyte hypertrophy depend at least partially on CyPA/CD147 inhibition.

Renin-Angiotensin-Aldosterone System Inhibition Increases Podocyte Derivation from Cells of Renin Lineage

PubMed Central

Lichtnekert, Julia; Kaverina, Natalya V.; Eng, Diana G.; Gross, Kenneth W.; Kutz, J. Nathan; Pippin, Jeffrey W.

2016-01-01

Because adult podocytes cannot proliferate and are therefore unable to self-renew, replacement of these cells depends on stem/progenitor cells. Although podocyte number is higher after renin-angiotensin-aldosterone system (RAAS) inhibition in glomerular diseases, the events explaining this increase are unclear. Cells of renin lineage (CoRL) have marked plasticity, including the ability to acquire a podocyte phenotype. To test the hypothesis that RAAS inhibition partially replenishes adult podocytes by increasing CoRL number, migration, and/or transdifferentiation, we administered tamoxifen to Ren1cCreERxRs-tdTomato-R CoRL reporter mice to induce permanent labeling of CoRL with red fluorescent protein variant tdTomato. We then induced experimental FSGS, typified by abrupt podocyte depletion, with a cytopathic antipodocyte antibody. RAAS inhibition by enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin-receptor blocker) in FSGS mice stimulated the proliferation of CoRL, increasing the reservoir of these cells in the juxtaglomerular compartment (JGC). Compared with water or hydralazine, RAAS inhibition significantly increased the migration of CoRL from the JGC to the intraglomerular compartment (IGC), with more glomeruli containing RFP+CoRL and, within these glomeruli, more RFP+CoRL. Moreover, RAAS inhibition in FSGS mice increased RFP+CoRL transdifferentiation in the IGC to phenotypes, consistent with those of podocytes (coexpression of synaptopodin and Wilms tumor protein), parietal epithelial cells (PAX 8), and mesangial cells (α8 integrin). These results show that in the context of podocyte depletion in FSGS, RAAS inhibition augments CoRL proliferation and plasticity toward three different glomerular cell lineages. PMID:27080979

Effects of angiotensin II type 2 receptor overexpression on the growth of hepatocellular carcinoma cells in vitro and in vivo.

PubMed

Du, Hongyan; Liang, Zhibing; Zhang, Yanling; Jie, Feilong; Li, Jinlong; Fei, Yang; Huang, Zhi; Pei, Nana; Wang, Suihai; Li, Andrew; Chen, Baihong; Zhang, Yi; Sumners, Colin; Li, Ming; Li, Hongwei

2013-01-01

Increasing evidence suggests that the renin-angiotensin system (RAS) plays an important role in tumorigenesis. The interaction between Angiotensin II (AngII) and angiotensin type 1 receptor (AT1R) may have a pivotal role in hepatocellular carcinoma (HCC) and therefore, AT1R blocker and angiotensin I-converting enzyme (ACE) inhibitors may have therapeutic potential in the treatment of hepatic cancer. Although the involvement of AT1R has been well explored, the role of the angiotensin II Type 2 receptor (AT2R) in HCC progression remains poorly understood. Thus, the aim of this study was to explore the effects of AT2R overexpression on HCC cells in vitro and in mouse models of human HCC. An AT2R recombinant adenoviral vector (Ad-G-AT2R-EGFP) was transduced into HCC cell lines and orthotopic tumor grafts. The results indicate that the high dose of Ad-G-AT2R-EGFP-induced overexpression of AT2R in transduced HCC cell lines produced apoptosis. AT2R overexpression in SMMC7721 cells inhibited cell proliferation with a significant reduction of S-phase cells and an enrichment of G1-phase cells through changing expression of CDK4 and cyclinD1. The data also indicate that overexpression of AT2R led to apoptosis via cell death signaling pathway that is dependent on activation of p38 MAPK, pJNK, caspase-8 and caspase-3 and inactivation of pp42/44 MAPK (Erk1/2). Finally, we demonstrated that moderately increasing AT2R expression could increase the growth of HCC tumors and the proliferation of HCC cells in vivo. Our findings suggest that AT2R overexpression regulates proliferation of hepatocellular carcinoma cells in vitro and in vivo, and the precise mechanisms of this phenomenon are yet to be fully determined.

Angiotensin II activates collagen type I gene in the renal vasculature of transgenic mice during inhibition of nitric oxide synthesis: evidence for an endothelin-mediated mechanism.

PubMed

Boffa, J J; Tharaux, P L; Placier, S; Ardaillou, R; Dussaule, J C; Chatziantoniou, C

1999-11-02

Hypertension is frequently associated with renal vascular fibrosis. The purpose of this study was to investigate whether angiotensin II (Ang II) is involved in this fibrogenic process. Experiments were performed on transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Hypertension was induced by chronic inhibition of NO synthesis (N(G)-nitro-L-arginine methyl ester, L-NAME). Procolalpha(2)(I) activity started to increase in the renal vasculature after 4 weeks of L-NAME treatment (P<0.01) and at 14 weeks reached 3- and 8-fold increases over control in afferent arterioles and glomeruli, respectively (P<0.001). Losartan, an AT(1) receptor antagonist, given simultaneously with L-NAME prevented the increase of procolalpha(2)(I) levels and attenuated the development of renal vascular fibrosis without normalizing systolic pressure increase. Because we found previously that endothelin mediated renal vascular fibrosis in the L-NAME model, the interaction between Ang II, endothelin, and procolalpha(2)(I) was investigated in ex vivo and short-term in vivo experiments. In both conditions, the Ang II-induced activation of procolalpha(2)(I) in renal cortex was blocked by an endothelin receptor antagonist. During chronic inhibition of NO, the collagen I gene becomes activated, leading to the development of renal vascular fibrosis. Ang II is a major player in this fibrogenic process, and its effect on collagen I gene is independent of systemic hemodynamics and is at least partly mediated by the profibrogenic action of endothelin.

Impact of Renin-Angiotensin Aldosterone System Inhibition on Serum Potassium Levels among Peritoneal Dialysis Patients.

PubMed

Ribeiro, Silvia Carreira; Figueiredo, Ana Elizabeth; Barretti, Pasqual; Pecoits-Filho, Roberto; de Moraes, Thyago Proença

2017-01-01

The chronic use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker has been associated with hyperkalemia in patients with reduced renal function even after the initiation of hemodialysis. Whether such medications may cause a similar effect in peritoneal dialysis patients is not well established. So, the aim of our study was to analyze the impact of renin-angiotensin-aldosterone inhibitors on the serum levels of potassium in a national cohort of peritoneal dialysis patients. A prospective, observational, nationwide cohort study was conducted. We identified all incident patients on peritoneal dialysis that had angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) prescribed for at least 3 months and a similar period of time without these medications. Patients were divided into 4 groups: Groups I and III correspond to patients using, respectively, an ACEi or ARB and then got the drug suspended; Groups II and IV started peritoneal dialysis without the use of any renin-angiotensin aldosterone system inhibitor and then got, respectively, an ACEi or ARB introduced. Changes in potassium serum levels were compared using 2 statistical approaches: (1) the non-parametric Wilcoxon test for repeated measures and (2) a crossover analysis. Mean potassium serum levels at the first phase of the study for Groups I, II, III, and IV were, respectively, 4.46 ± 0.79, 4.33 ± 0.78, 4.41 ± 0.63, and 4.44 ± 0.56. Changes in mean potassium serum levels for Groups I, II, III, and IV were -0.10 ± 0.60, 0.02 ± 0.56, -0.06 ± 0.46, and 0.03 ± 0.50, respectively. The use of ACEi and ARB was not associated with a greater risk for hyperkalemia in stable peritoneal dialysis patients independently of residual renal function. © 2017 S. Karger AG, Basel.

Angiotensin-I is Largely Converted to Angiotensin-(1-7) and Angiotensin-(2-10) by Isolated Rat Glomeruli

PubMed Central

JC, Velez; KJ, Ryan; CE, Harbeson; AM, Bland; MN, Budisavljevic; JM, Arthur; WR, Fitzgibbon; JR, Raymond; MG, Janech

2009-01-01

Intraglomerular renin-angiotensin system (RAS) enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (ANG)-II detection, ignoring the generation of other ANG-I-derived metabolites, some of which may cross-react with ANG-II. Therefore, our aim was to examine the metabolism of ANG-I in freshly isolated intact glomeruli using MALDI-TOF mass spectrometry (MS) as an analytical method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 μM ANG-I for 15 - 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by MALDI-TOF MS/MS or linear-trap-quadrupole MS. Peaks were quantified using customized valine-13C.15N-labeled peptides as standards. The most prominent peaks resulting from ANG-I cleavage were 899 and 1181 m/z, corresponding to ANG-1-7 and ANG-2-10, respectively. Smaller peaks for ANG-II, ANG-1-9 and ANG-3-10 also were detected. The disappearance of ANG-I was significantly reduced during inhibition of aminopeptidase-A or neprilysin. In contrast, captopril did not alter ANG-I degradation. Furthermore, during simultaneous inhibition of aminopeptidase-A and neprilysin, the disappearance of ANG-I was markedly attenuated compared to all other conditions. These results suggest that there is prominent intraglomerular conversion of ANG-I to ANG-2-10 and ANG-1-7, mediated by aminopeptidase-A and neprilysin, respectively. Formation of these alternative ANG peptides may be critical to counterbalance the local actions of ANG-II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for ANG-II mediated glomerular diseases. PMID:19289651

Natriuretic peptide receptor-C activation attenuates angiotensin II-induced enhanced oxidative stress and hyperproliferation of aortic vascular smooth muscle cells.

PubMed

Madiraju, Padma; Hossain, Ekhtear; Anand-Srivastava, Madhu B

2018-02-07

We showed previously that natriuretic peptide receptor-C (NPR-C) agonist, C-ANP 4-23 , attenuated the enhanced expression of Giα proteins in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) through the inhibition of enhanced oxidative stress. Since the enhanced levels of endogenous angiotensin II (Ang II) contribute to the overexpression of Giα proteins and augmented oxidative stress in VSMC from SHR, the present study was undertaken to investigate if C-ANP 4-23 could also attenuate angiotensin II (Ang II)-induced oxidative stress and associated signaling. Ang II treatment of aortic VSMC augmented the levels of superoxide anion (O 2 - ), NADPH oxidase activity, and the expression of NADPH oxidase subunits and C-ANP 4-23 treatment attenuated all these to control levels. In addition, Ang II-induced enhanced levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyl content were also attenuated toward control levels by C-ANP 4-23 treatment. On the other hand, Ang II inhibited the levels of nitric oxide (NO) and augmented the levels of peroxynitrite (OONO - ) in VSMC which were restored to control levels by C-ANP 4-23 treatment. Furthermore, C-ANP 4-23 treatment attenuated Ang II-induced enhanced expression of Giα proteins, phosphorylation of p38, JNK, and ERK 1,2 as well as hyperproliferation of VSMC as determined by DNA synthesis, and metabolic activity. These results indicate that C-ANP 4-23 , via the activation of NPR-C, attenuates Ang II-induced enhanced nitroxidative stress, overexpression of Giα proteins, increased activation of the p38/JNK/ERK 1,2 signaling pathways, and hyperproliferation of VSMC. It may be suggested that C-ANP 4-23 could be used as a therapeutic agent in the treatment of vascular remodeling associated with hypertension and atherosclerosis.

Role of vascular smooth muscle PPARγ in regulating AT1 receptor signaling and angiotensin II-dependent hypertension.

PubMed

Carrillo-Sepulveda, Maria Alicia; Keen, Henry L; Davis, Deborah R; Grobe, Justin L; Sigmund, Curt D

2014-01-01

Peroxisome proliferator activated receptor γ (PPARγ) has been reported to play a protective role in the vasculature; however, the underlying mechanisms involved are not entirely known. We previously showed that vascular smooth muscle-specific overexpression of a dominant negative human PPARγ mutation in mice (S-P467L) leads to enhanced myogenic tone and increased angiotensin-II-dependent vasoconstriction. S-P467L mice also exhibit increased arterial blood pressure. Here we tested the hypotheses that a) mesenteric smooth muscle cells isolated from S-P467L mice exhibit enhanced angiotensin-II AT1 receptor signaling, and b) the increased arterial pressure of S-P467L mice is angiotensin-II AT1 receptor dependent. Phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (ERK1/2) was robustly increased in mesenteric artery smooth muscle cell cultures from S-P467L in response to angiotensin-II. The increase in ERK1/2 activation by angiotensin-II was blocked by losartan, a blocker of AT1 receptors. Angiotensin-II-induced ERK1/2 activation was also blocked by Tempol, a scavenger of reactive oxygen species, and correlated with increased Nox4 protein expression. To investigate whether endogenous renin-angiotensin system activity contributes to the elevated arterial pressure in S-P467L, non-transgenic and S-P467L mice were treated with the AT1 receptor blocker, losartan (30 mg/kg per day), for 14-days and arterial pressure was assessed by radiotelemetry. At baseline S-P467L mice showed a significant increase of systolic arterial pressure (142.0 ± 10.2 vs 129.1 ± 3.0 mmHg, p<0.05). Treatment with losartan lowered systolic arterial pressure in S-P467L (132.2 ± 6.9 mmHg) to a level similar to untreated non-transgenic mice. Losartan also lowered arterial pressure in non-transgenic (113.0 ± 3.9 mmHg) mice, such that there was no difference in the losartan-induced depressor response between groups (-13.53 ± 1.39 in S-P467L vs -16.16 ± 3.14 mmHg in

Conditional expression of the type 2 angiotensin II receptor in mesenchymal stem cells inhibits neointimal formation after arterial injury.

PubMed

Feng, Jian; Liu, Jian-Ping; Miao, Li; He, Guo-Xiang; Li, De; Wang, Hai-Dong; Jing, Tao

2014-10-01

Percutaneous coronary interventions (PCIs) are an effective treatment for obstructive coronary artery diseases. However, the procedure's success is limited by remodeling and formation of neointima. In the present study, we engineered rat mesenchymal stem cells (MSCs) to express type 2 angiotensin II receptor (AT2R) using a tetracycline-regulated system that can strictly regulate AT2R expression. We tested the ability of the modified MSCs to reduce neointima formation following arterial injury. We subjected rats to balloon injury, and reverse transcriptase polymerase chain reaction (RT-PCR) indicated no significant AT2R expression in normal rat arteries. Low expression of AT2R was observed at 28 days after balloon-induced injury. Interestingly, MSCs alone were unable to reduce neointimal hyperplasia after balloon-induced injury; after transplantation of modified MSCs, doxycycline treatment significantly upregulated neointimal AT2R expression and inhibited osteopontin mRNA expression, as well as neointimal formation. Taken together, these results suggest that transplantation of MSCs conditionally expressing AT2R could effectively suppress neointimal hyperplasia following balloon-induced injury. Therefore, MSCs with a doxycycline-controlled gene induction system may be useful for the management of arterial injury after PCI.

STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.

PubMed

Chen, Lei; Zhao, Lin; Samanta, Anweshan; Mahmoudi, Seyed Morteza; Buehler, Tanner; Cantilena, Amy; Vincent, Robert J; Girgis, Magdy; Breeden, Joshua; Asante, Samuel; Xuan, Yu-Ting; Dawn, Buddhadeb

2017-01-01

Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and β-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and β-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling.

STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis

PubMed Central

Samanta, Anweshan; Mahmoudi, Seyed Morteza; Buehler, Tanner; Cantilena, Amy; Vincent, Robert J.; Girgis, Magdy; Breeden, Joshua; Asante, Samuel; Xuan, Yu-Ting

2017-01-01

Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and β-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and β-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling. PMID:28686615

Angiotensin Converting Enzyme Regulates Cell Proliferation and Migration

PubMed Central

Carvalho, Clarissa Coelho; Florentino, Rodrigo Machado; França, Andressa; Matias, Eveline; Guimarães, Paola Bianchi; Batista, Carolina; Freire, Valder; Carmona, Adriana Karaoglanovic; Pesquero, João Bosco; de Paula, Ana Maria; Foureaux, Giselle; Leite, Maria de Fatima

2016-01-01

Background The angiotensin-I converting enzyme (ACE) plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II). More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet. Aim Therefore, our aim was to examine the role of ACE in tumor cell proliferation and migration. Results We found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC), and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5) showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril) or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein. Conclusion ACE activation regulates melanoma cell proliferation and migration. PMID:27992423

Increased sensitivity to angiotensin II is present postpartum in women with a history of hypertensive pregnancy.

PubMed

Saxena, Aditi R; Karumanchi, S Ananth; Brown, Nancy J; Royle, Caroline M; McElrath, Thomas F; Seely, Ellen W

2010-05-01

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P<0.05). Women with a history of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus -18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

Enhancement of noradrenaline release by angiotensin II and bradykinin in mouse atria: evidence for cross-talk between Gq/11 protein- and Gi/o protein-coupled receptors

PubMed Central

Cox, S L; Schelb, V; Trendelenburg, A U; Starke, K

2000-01-01

The interaction between α2-autoreceptors and receptors for angiotensin (AT1) and bradykinin (B2) was studied in mouse isolated atria. The preparations were labelled with [3H]-noradrenaline and then superfused with desipramine-containing medium and stimulated electrically. Angiotensin II (10−11–10−7 M), angiotensin III (10−10–10−6 M) and bradykinin (10−11–10−7 M) enhanced the evoked overflow of tritium when preparations were stimulated with conditions that led to marked α2-autoinhibition (120 pulses at 3 Hz), but not when stimulated with conditions that led to little α2-autoinhibition (20 pulses at 50 Hz). Blockade of α-adrenoceptors by phentolamine (1 or 10 μM) reduced or abolished the effect of angiotensin II and bradykinin on the overflow response to 120 pulses at 3 Hz. Addition of the δ-opioid agonist [D-Ser2]-leucine enkephalin-Thr (DSLET, 0.1 μM), or of neuropeptide Y (0.1 μM), together with phentolamine, restored the effect of angiotensin II and bradykinin. The β-adrenoceptor agonist terbutaline (10−9–10−4 M) enhanced the evoked overflow of tritium irrespective of the degree of autoinhibition. The experiments show that (i) a marked prejunctional facilitatory effect of angiotensin and bradykinin in mouse isolated atria requires prejunctional α2-autoinhibition; (ii) in the absence of α2-autoinhibition, activation of other prejunctional Gi/o protein-coupled reeptors, namely opioid and neuropeptide Y receptors, restores a marked effect of angiotensin II and bradykinin; and (iii) the facilitatory effect of terbutaline is not dependent upon the degree of α2-autoinhibition. The findings indicate that the major part of the release-enhancing effect elicited through prejunctional Gq/11 protein-coupled receptors is due to disruption of an ongoing, α2-autoreceptor-triggered Gi/o protein mediated inhibition. PMID:10725257

Des-aspartate-angiotensin I causes specific release of PGE2 and PGI2 in HUVEC via the angiotensin AT1 receptor and biased agonism.

PubMed

Wen, Qiang; Lee, Kok-Onn; Sim, Sai-Zhen; Xu, Xiao-Guang; Sim, Meng-Kwoon

2015-12-05

DAA-I (des-aspartate-angiotensin I), an endogenous angiotensin, had been shown earlier to ameliorate animal models of cardiovascular diseases via the angiotensin AT1 receptor and prostaglandins. The present study investigated further the action of DAA-I on the release of PGE2, PGI2, PGF2α and TXA2 in HUVEC. 10(-11)-10(-8)M DAA-I and 15min incubation specifically released PGE2 and PGI2. The release was inhibited by losartan and indomethacin but not by PD123319 and NS398 indicating that the angiotensin AT1 receptor and COX-1 mediate the release. At concentrations higher than 10(-7)M, DAA-I mimics the action of angiotensin II by releasing TXA2 but had no effect on the production of PGF2α. At similar concentrations and 4h incubation, DAA-I increased the release of the 4 prostaglandins via the angiotensin AT1 receptor and COX-2, again mimicking the action of angiotensin II. HUVEC that were preincubated with DAA-I or angiotensin II, released similar profiles of prostaglandins when incubated with arachidonic acid after the angiotensin had been washed off. We postulate that the internalized DAA-I/receptor complex remains active and mediates the conversion of arachidonic acid to the respective prostaglandins. The release of PGE2 and PGI2 via the angiotensin AT1 receptor and COX-1 is a novel specific action of DAA-I and is likely responsible for its beneficial effects seen in earlier studies. This specific action is definable as a biased agonism of the angiotensin AT1 receptor, which identifies DAA-I as a novel biased agonist and potential therapeutic that is able to produce specific prostaglandins at nanomolar concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Sulforaphane protects H9c2 cardiomyocytes from angiotensin II-induced hypertrophy.

PubMed

Wu, Q-Q; Zong, J; Gao, L; Dai, J; Yang, Z; Xu, M; Fang, Y; Ma, Z-G; Tang, Q-Z

2014-05-01

Cardiac hypertrophy is an adaptive process of the heart in response to various stimuli, but sustained cardiac hypertrophy will finally lead to heart failure. Sulforaphane-extracted from cruciferous vegetables of the genus Brassica such as broccoli, brussels sprouts, and cabbage-has been evaluated for its anticarcinogenic and antioxidant effects. To investigate the effect of sulforaphane on angiotensin II (Ang II)-induced cardiac hypertrophy in vitro. Embryonic rat heart-derived H9c2 cells were co-incubated with sulforaphane and Ang II. The cell surface area and mRNA levels of hypertrophic markers were measured to clarify the effect of sulforaphane on cardiac hypertrophy. The underlying mechanism was further investigated by detecting the activation of Akt and NF-κB signaling pathways. We found that H9c2 cells pretreated with sulforaphane were protected from Ang II-induced hypertrophy. The increasing mRNA levels of ANP, BNP, and β-MHC in Ang II-stimulated cells were also down-regulated after sulforaphane treatment. Moreover, sulforaphane repressed the Ang II-induced phosphorylation of Akt, GSK3β, mTOR, eIF4e, as well as of IκBα and NF-κB. Based on our results, sulforaphane attenuates Ang II-induced hypertrophy of H9c2 cardiomyocytes mediated by the inhibition of intracellular signaling pathways including Akt and NF-κB.

Gestational Exposure to Elevated Testosterone Levels Induces Hypertension via Heightened Vascular Angiotensin II Type 1 Receptor Signaling in Rats1

PubMed Central

Chinnathambi, Vijayakumar; More, Amar S.; Hankins, Gary D.; Yallampalli, Chandra; Sathishkumar, Kunju

2014-01-01

ABSTRACT Pre-eclampsia is a life-threatening pregnancy disorder whose pathogenesis remains unclear. Plasma testosterone levels are elevated in pregnant women with pre-eclampsia and polycystic ovary syndrome, who often develop gestational hypertension. We tested the hypothesis that increased gestational testosterone levels induce hypertension via heightened angiotensin II signaling. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate from Gestational Day 15 to 19 to induce a 2-fold increase in plasma testosterone levels, similar to levels observed in clinical conditions like pre-eclampsia. A subset of rats in these two groups was given losartan, an angiotensin II type 1 receptor antagonist by gavage during the course of testosterone exposure. Blood pressure levels were assessed through a carotid arterial catheter and endothelium-independent vascular reactivity through wire myography. Angiotensin II levels in plasma and angiotensin II type 1 receptor expression in mesenteric arteries were also examined. Blood pressure levels were significantly higher on Gestational Day 20 in testosterone-treated dams than in controls. Treatment with losartan during the course of testosterone exposure significantly attenuated testosterone-induced hypertension. Plasma angiotensin II levels were not significantly different between control and testosterone-treated rats; however, elevated testosterone levels significantly increased angiotensin II type 1 receptor protein levels in the mesenteric arteries. In testosterone-treated rats, mesenteric artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K+ depolarization and phenylephrine were unaffected. The results demonstrate that elevated testosterone during gestation induces hypertension in pregnant rats via heightened angiotensin II type 1 receptor-mediated signaling, providing a molecular mechanism linking elevated maternal testosterone levels with

Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells.

PubMed

Min, Li-Juan; Mogi, Masaki; Li, Jian-Mei; Iwanami, Jun; Iwai, Masaru; Horiuchi, Masatsugu

2005-09-02

Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10(-12) mol/L) and with a lower dose of Ang II (10(-10) mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.

Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine.

PubMed

Baum, Michel

2016-02-15

Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100- to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10(-8) M ANG II to the lumen inhibited mTAL chloride transport (220 ± 19 to 165 ± 25 pmol·mm(-1)·min(-1), P < 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10(-6) M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 ± 18 to 364 ± 42 pmol·mm(-1)·min(-1) (P < 0.05). Stimulation of chloride transport by luminal ANG II was also observed with 10(-3) M bath dibutyryl cAMP in the bathing solution and bath isoproterenol. A bath of 10(-5) H-89 blocked the stimulation of chloride transport by norepinephrine and prevented the effect of luminal ANG II to either stimulate or inhibit chloride transport. Bath phentolamine, an α-adrenergic agonist, also prevented the decrease in mTAL chloride transport by luminal ANG II. Thus luminal ANG II increases chloride transport with basolateral norepinephrine; an effect likely mediated by stimulation of cAMP. Alpha-1 adrenergic stimulation prevents the inhibition of chloride transport by luminal ANG II. Copyright © 2016 the American Physiological Society.

Role of H2O2 in hypertension, renin-angiotensin system activation and renal medullary disfunction caused by angiotensin II

PubMed Central

Sousa, T; Oliveira, S; Afonso, J; Morato, M; Patinha, D; Fraga, S; Carvalho, F; Albino-Teixeira, A

2012-01-01

BACKGROUND AND PURPOSE Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H2O2) contribute to hypertension. We examined whether H2O2 mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II). EXPERIMENTAL APPROACH Ang II (200 ng·kg−1·min−1) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg−1·day−1) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H2O2, angiotensin AT1 receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H2O2 and angiotensinogen were also measured. KEY RESULTS Ang II increased H2O2, AT1 receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H2O2 levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT1 receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H2O2 levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen. CONCLUSIONS AND IMPLICATIONS The renal medulla is a major target for Ang II-induced redox dysfunction. H2O2 appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H2O2 levels may provide future grounds for the treatment of hypertension. PMID:22452317

Distortion of maternal-fetal angiotensin II type 1 receptor allele transmission in pre-eclampsia.

PubMed Central

Morgan, L; Crawshaw, S; Baker, P N; Brookfield, J F; Broughton Pipkin, F; Kalsheker, N

1998-01-01

OBJECTIVE: To investigate the fetal angiotensin II type 1 receptor genotype in pre-eclampsia. DESIGN: Case-control study. POPULATION: Forty-one maternal-fetal pairs from pre-eclamptic pregnancies and 80 maternal-fetal pairs from normotensive pregnancies. METHODS: Maternal and fetal DNA was genotyped at three diallelic polymorphisms, at nucleotides 573, 1062, and 1166, in the coding exon of the angiotensin II type 1 receptor gene, and at a dinucleotide repeat polymorphism in its 3' flanking region. RESULTS: Allele and genotype frequencies at the four polymorphic regions investigated did not differ between pre-eclamptic and normotensive groups, in either fetal or maternal samples. Mothers heterozygous for the dinucleotide repeat allele designated A4 transmitted this allele to the fetus in 15 of 18 informative pre-eclamptic pregnancies and in eight of 26 normotensive pregnancies. This was greater than the expected probability in pre-eclamptic pregnancies (p=0.04) and less than expected in normotensive pregnancies (p<0.005). The 573T variant, which is in partial linkage disequilibrium with the A4 allele, showed a similar distortion of maternal-fetal transmission. CONCLUSION: Angiotensin II type 1 receptor gene expression in the fetus may contribute to the aetiology of pre-eclampsia. It is unclear whether susceptibility is conferred by the fetal genotype acting alone, or by allele sharing by mother and fetus. Possible mechanisms for the effect of the angiotensin II type 1 receptor gene are suggested by the association of the 573T variant with low levels of surface receptor expression on platelets. If receptor expression is similarly genetically determined in the placenta, responsiveness to angiotensin II may be affected, with the potential to influence placentation or placental prostaglandin secretion. PMID:9719367

Molecular recognition and regulation of human angiotensin-I converting enzyme (ACE) activity by natural inhibitory peptides

PubMed Central

Masuyer, Geoffrey; Schwager, Sylva L. U.; Sturrock, Edward D.; Isaac, R. Elwyn; Acharya, K. Ravi

2012-01-01

Angiotensin-I converting enzyme (ACE), a two-domain dipeptidylcarboxypeptidase, is a key regulator of blood pressure as a result of its critical role in the renin-angiotensin-aldosterone and kallikrein-kinin systems. Hence it is an important drug target in the treatment of cardiovascular diseases. ACE is primarily known for its ability to cleave angiotensin I (Ang I) to the vasoactive octapeptide angiotensin II (Ang II), but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a physiological modulator of hematopoiesis. For the first time we provide a detailed biochemical and structural basis for the domain selectivity of the natural peptide inhibitors of ACE, bradykinin potentiating peptide b and Ang II. Moreover, Ang II showed selective competitive inhibition of the carboxy-terminal domain of human somatic ACE providing evidence for a regulatory role in the human renin-angiotensin system (RAS). PMID:23056909

A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker.

PubMed

Hashemzadeh, Mehrnoosh; Park, Shery; Ju, Hee; Movahed, Mohammad R

2013-12-01

Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

Csk regulates angiotensin II-induced podocyte apoptosis.

PubMed

Zhang, Lu; Ren, Zhilong; Yang, Qian; Ding, Guohua

2016-07-01

Increasing data have shown that angiotensin II (Ang II) perpetuates podocyte injury and promotes progression to end-stage kidney disease. The mechanism underlying Ang II-induced podocyte apoptosis has not been established. C-terminal Src kinase (Csk) is a cytoplasmic kinase that interacts with scaffolding proteins involved in cell growth, adhesion, and polarization, and the role of Csk in regulating cellular apoptosis has gradually attracted attention. This study evaluates the role of Csk in Ang II-induced podocyte apoptosis. In vivo, Wistar rats were randomly subjected to a normal saline or Ang II infusion. In vitro, we exposed differentiated mouse podocytes to Ang II. Ang II increased Csk expression and induced podocyte apoptosis, stimulated Csk translocation and binding to Caveolin-1, and stimulated decreased Fyn pY416, increased Fyn pY529, and nephrin dephosphorylation. Csk knockdown prevented Ang II-induced podocyte apoptosis, reduced Fyn kinase inactivation, and increased the interaction between nephrin and the activated form of Fyn, accompanied by a reduced interaction between Csk and Caveolin-1. These findings indicate that Ang II induces podocyte injury via a Csk-dependent pathway.

Activation of D4 dopamine receptor decreases AT1 angiotensin II receptor expression in rat renal proximal tubule cells

PubMed Central

Chen, Ken; Deng, Kun; Wang, Xiaoyan; Wang, Zhen; Zheng, Shuo; Ren, Hongmei; He, Duofen; Han, Yu; Asico, Laureano D.; Jose, Pedro A.; Zeng, Chunyu

2014-01-01

The dopaminergic and renin angiotensin systems interact to regulate blood pressure. Disruption of the D4 dopamine receptor gene in mice produces hypertension that is associated with increased renal AT1 receptor expression. We hypothesize that the D4 receptor can inhibit AT1 receptor expression and function in renal proximal tubules (RPTs) cells from Wistar-Kyoto (WKY) rats but the D4 receptor regulation of AT1 receptor is aberrant in RPT cells from spontaneously hypertensive rats (SHRs). The D4 receptor agonist, PD168077, decreased AT1 receptor protein expression in a time and concentration-dependent manner in WKY cells. By contrast, in SHR cells, PD168077 increased AT1 receptor protein expression. The inhibitory effect of D4 receptor on AT1 receptor expression in WKY cells was blocked by a calcium channel blocker, nicardipine, or calcium-free medium, indicating that calcium is involved in the D4 receptor-mediated signaling pathway. Angiotensin II increased Na+-K+ ATPase activity in WKY cells. Pretreatment with PD168077 decreased the stimulatory effect of angiotensin II on Na+-K+ ATPase activity in WKY cells. In SHR cells, the inhibitory effect of D4 receptor on angiotensin II-mediated stimulation of Na+-K+ ATPase activity was aberrant; pretreatment with PD168077 augmented the stimulatory effect of AT1 receptor on Na+-K+ ATPase activity in SHR cells. This was confirmed in vivo; pre-treatment with PD128077 for one week augmented the anti-hypertensive and natriuretic effect of losartan in SHRs but not in WKY rats. We suggest that an aberrant interaction between D4 and AT1 receptors may play a role in the abnormal regulation of sodium excretion in hypertension. PMID:25368031

Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas receptor axis.

PubMed

Li, Yonghong; Cai, Shanglang; Wang, Qixin; Zhou, Jingwei; Hou, Bo; Yu, Haichu; Ge, Zhiming; Guan, Renyan; Liu, Xu

2016-05-15

The role of the Mas receptor in the activity of valsartan against intimal hyperplasia is unclear. Herein, we investigated the role of the angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis on the activity of valsartan against intimal hyperplasiain balloon-injured rat aortic arteries. Wistar rats were randomized equally into the sham control group, injured group, and injured plus valsartan (20 mg/kg/d)-treated group. Valsartan significantly attenuated the vascular smooth muscle cell proliferation and intimal and medial thickening on days 14 and 28 after injury. The angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression were significantly decreased in the injured rats, compared to the uninjured rats; meanwhile, the angiotensin II level as well as the ACE and AT1 receptor mRNA/protein expression were increased (all P < 0.05 or < 0.01). Additionally, the p-ERK protein expression was increased (P < 0.01). Treatment with valsartan significantly increased the angiotensin-(1-7) levels as well as ACE2 and Mas receptor mRNA/protein expression but decreased the angiotensin II level, ACE and AT1 receptor mRNA/protein expression, as well as the p-ERK protein expression, compared to the injured group (all P < 0.05 or < 0.01). These results suggest that valsartan attenuates neointimal hyperplasiain balloon-injured rat aortic arteries through activation of the ACE2-angiotensin-(1-7)-Mas axis as well as inhibition of the ACE-angiotensin II-AT1 and p-ERK pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

PubMed

Zhang, Jia-Ying; Yin, Ying; Ni, Li; Long, Quan; You, Li; Zhang, Qian; Lin, Shan-Yan; Chen, Jing

2016-11-01

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

A Low-Protein Diet Enhances Angiotensin II Production in the Lung of Pregnant Rats but Not Nonpregnant Rats

PubMed Central

Gao, Haijun; Tanchico, Daren Tubianosa; Yallampalli, Uma; Yallampalli, Chandrasekhar

2016-01-01

Pulmonary angiotensin II production is enhanced in pregnant rats fed a low-protein (LP) diet. Here we assessed if LP diet induces elevations in angiotensin II production in nonpregnant rats and whether Ace expression and ACE activity in lungs are increased. Nonpregnant rats were fed a normal (CT) or LP diet for 8, 12, or 17 days and timed pregnant rats fed for 17 days from Day 3 of pregnancy. Plasma angiotensin II, expressions of Ace and Ace2, and activities of these proteins in lungs, kidneys, and plasma were measured. These parameters were compared among nonpregnant rats or between nonpregnant and pregnant rats fed different diets. Major findings are as follows: (1) plasma angiotensin II levels were slightly higher in the LP than CT group on Days 8 and 12 in nonpregnant rats; (2) expression of Ace and Ace2 and abundance and activities of ACE and ACE2 in lungs, kidneys, and plasma of nonpregnant rats were unchanged by LP diet except for minor changes; (3) the abundance and activities of ACE in lungs of pregnant rats fed LP diet were greater than nonpregnant rats, while those of ACE2 were decreased. These results indicate that LP diet-induced increase in pulmonary angiotensin II production depends on pregnancy. PMID:27195150

Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gu, Jun; Liu, Xu, E-mail: xkliuxu@yahoo.cn; Wang, Quan-xing, E-mail: shmywqx@126.com

2012-10-01

The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated proteinmore » kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.« less

The Attenuation of Central Angiotensin II-dependent Pressor Response and Intra-neuronal Signaling by Intracarotid Injection of Nanoformulated Copper/Zinc Superoxide Dismutase

PubMed Central

Rosenbaugh, Erin G.; Roat, James; Gao, Lie; Yang, Rui-Fang; Manickam, Devika S.; Yin, Jing-Xiang; Schultz, Harold D.; Bronich, Tatiana K.; Batrakova, Elena V.; Kabanov, Alexander V.; Zucker, Irving H.; Zimmerman, Matthew C.

2010-01-01

Adenoviral-mediated overexpression of the intracellular superoxide (O2•−) scavenging enzyme copper/zinc superoxide dismutase (CuZnSOD) in the brain attenuates central angiotensin II (AngII)-induced cardiovascular responses. However, the therapeutic potential for adenoviral vectors is weakened by toxicity and the inability of adenoviral vectors to target the brain following peripheral administration. Therefore, we developed a non-viral delivery system in which CuZnSOD protein is electrostatically bound to a synthetic poly(ethyleneimine)-poly(ethyleneglycol) (PEI-PEG) polymer to form a polyion complex (CuZnSOD nanozyme). We hypothesized that PEI-PEG polymer increases transport of functional CuZnSOD to neurons, which inhibits AngII intra-neuronal signaling. The AngII-induced increase in O2•−, as measured by dihydroethidium fluorescence and electron paramagnetic resonance spectroscopy, was significantly inhibited in CuZnSOD nanozyme-treated neurons compared to free CuZnSOD- and non-treated neurons. CuZnSOD nanozyme also attenuated the AngII-induced inhibition of K+ current in neurons. Intracarotid injection of CuZnSOD nanozyme into rabbits significantly inhibited the pressor response of intracerebroventricular-delivered AngII; however, intracarotid injection of free CuZnSOD or PEI-PEG polymer alone failed to inhibit this response. Importantly, neither the PEI-PEG polymer alone nor the CuZnSOD nanozyme induced neuronal toxicity. These findings indicate that CuZnSOD nanozyme inhibits AngII intra-neuronal signaling in vitro and in vivo. PMID:20378166

Regulation of oxygen utilization by angiotensin II in chronic kidney disease

PubMed Central

Deng, Aihua; Tang, Tong; Singh, Prabhleen; Wang, Chen; Satriano, Joe; Thomson, Scott C; Blantz, Roland C

2010-01-01

Angiotensin II (ANG II) blockade delays progression of chronic kidney disease (CKD) by modifying intrarenal hemodynamics, but the effect on metabolic adaptations has not been examined. Using renal ablation/infarction (A/I) model of CKD in rats at one week, the effects of ANG II blockade by captopril (CAP) and losartan (LOS) on renal O2 consumption (QO2), renal nitric oxide (NO) activity and nitric oxide synthase (NOS) protein expression was examined. A/I kidneys exhibited proteinuria, reduced GFR, renal blood flow (RBF) and NOS-1 protein expression, while QO2 factored by sodium reabsorption (QO2/TNa) was markedly increased. CAP + LOS treatment increased GFR, RBF, and TNa, while QO2 remained unchanged, thus normalizing QO2/TNa. NOS-1 expression was normalized with CAP + LOS, as was proteinuria. Triple antihypertensive therapy administered to control for the blood pressure reduction, and lysine administration to increase GFR and RBF, did not normalize QO2/TNa, suggesting a specific effect of ANG II in elevating QO2/TNa. NOS blockade, to test functional NO activity on QO2 and QO2/TNa, increased QO2 in shams, but not in untreated A/I. The increase in QO2 was restored in CAP + LOS treated A/I. CAP + LOS treatment normalized the increased QO2/TNa and functional NO activity in A/I independent of the blood pressure and GFR effects, providing evidence for an additional mechanism underlying the benefits of ANG II inhibition therapy. PMID:18818681

Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase.

PubMed

Hornig, B; Landmesser, U; Kohler, C; Ahlersmann, D; Spiekermann, S; Christoph, A; Tatge, H; Drexler, H

2001-02-13

Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT(1)-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT(1)-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-L-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and losartan (each group P<0.01), and in particular, the portion of FDD mediated by NO, ie, inhibited by L-NMMA, was increased by >75% (each group P<0.01). Vitamin C improved FDD initially, an effect that was lost after ramipril or losartan. After therapy, EC-SOD activity was increased by >200% in both groups (ACEI, 14.4+/-1.1 versus 3.8+/-0.9 and AT(1)-A, 13.5+/-1.0 versus 3.9+/-0.9 U. mL(-1). min(-1); each P<0.01). CONCLUSIONS-Four weeks of therapy with ramipril or losartan improves endothelial function to similar extents in patients with CAD by increasing the bioavailability of NO. Our results suggest that beneficial long-term effects of interference with the renin-angiotensin system may be related to reduction of oxidative stress within the arterial wall, mediated in part by increased EC-SOD activity.

Azilsartan: a newly approved angiotensin II receptor blocker.

PubMed

Lam, Sum

2011-01-01

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality. Blood pressure control is essential to prevent end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Azilsartan is the eighth angiotensin II receptor blocker approved for the management of hypertension, alone or in combination with other agents. At the approved dosage, it reduces systolic blood pressure by 12 to 15 mm Hg and diastolic blood pressure by 7 to 8 mm Hg. A higher dose of azilsartan (80 mg) was superior to valsartan 320 mg or olmesartan 40 mg in lowering systolic blood pressure in short-term studies. Additional blood pressure reduction is expected when azilsartan is used adjunctively with a diuretic. However, the effects of azilsartan on cardiovascular morbidity or mortality are still lacking. Azilsartan is well tolerated; the most common side effects are headache and diarrhea. No cases of hyperkalemia have been reported in 6-week clinical trials. Worsening of renal function and hypotension should be monitored, particularly in those with baseline risk factors. It is unknown whether azilsartan would join angiotensin-converting enzyme inhibitors and other angiotensin receptor blockers as the preferred hypertensive agents for end-organ protection. At this time, azilsartan should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or cannot tolerate other antihypertensive agents, including dry cough induced by angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme inhibition improves cardiac fatty acid metabolism in patients with congestive heart failure.

PubMed

Yamauchi, S; Takeishi, Y; Minamihaba, O; Arimoto, T; Hirono, O; Takahashi, H; Miyamoto, T; Nitobe, J; Nozaki, N; Tachibana, H; Watanabe, T; Fukui, A; Kubota, I

2003-08-01

This study aimed to examine whether angiotensin-converting enzyme (ACE) inhibition improved cardiac fatty acid metabolism in patients with congestive heart failure (CHF). Myocardial 123I-beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging was performed in 25 patients with CHF and in 10 control subjects. Myocardial 123I-BMIPP images were obtained 30 min and 4 h after tracer injection. The heart-to-mediastinum (H/M) ratio of 123I-BMIPP uptake and the washout rate of 123I-BMIPP from the myocardium were calculated. Patients were given enalapril for 6 months, and 123I-BMIPP imaging was repeated. H/M ratios on early and delayed images were lower in CHF patients than in normal controls (P<0.01). The washout rate of 123I-BMIPP from the myocardium was faster in CHF patients than in controls (P<0.01). As the severity of the New York Heart Association (NYHA) functional class increased, the H/M ratio decreased and the washout rate increased. The washout rate of 123I-BMIPP was inversely correlated with left ventricular fractional shortening (R=-0.62, P<0.01). ACE inhibition with enalapril increased the H/M ratio on delayed images (P<0.05) and reduced the washout rate of 123I-BMIPP (P<0.05) in CHF patients. These data suggest that: (1) angiotensin II-mediated intracellular signalling activation may be a possible mechanism for the decreased myocardial uptake and enhanced washout of 123I-BMIPP in heart failure patients; and (2) the improvement in fatty acid metabolism by ACE inhibition may represent a new mechanism for the beneficial effect of this therapy in heart failure.

Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).

PubMed

Xu, Zheng; Li, Weixin; Han, Jibo; Zou, Chunpeng; Huang, Weijian; Yu, Weihui; Shan, Xiaoou; Lum, Hazel; Li, Xiaokun; Liang, Guang

2017-03-21

Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2 -/- mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney.

PubMed

Onozato, Maristela Lika; Tojo, Akihiro; Kobayashi, Naohiko; Goto, Atsuo; Matsuoka, Hiroaki; Fujita, Toshiro

2007-05-01

Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF). Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

Dietary sodium deprivation evokes activation of brain regional neurons and down-regulation of angiotensin II type 1 receptor and angiotensin-convertion enzyme mRNA expression.

PubMed

Lu, B; Yang, X J; Chen, K; Yang, D J; Yan, J Q

2009-12-15

Previous studies have indicated that the renin-angiotensin-aldosterone system (RAAS) is implicated in the induction of sodium appetite in rats and that different dietary sodium intakes influence the mRNA expression of central and peripheral RAAS components. To determine whether dietary sodium deprivation activates regional brain neurons related to sodium appetite, and changes their gene expression of RAAS components of rats, the present study examined the c-Fos expression after chronic exposure to low sodium diet, and determined the relationship between plasma and brain angiotensin I (ANG I), angiotensin II (ANG II) and aldosterone (ALD) levels and the sodium ingestive behavior variations, as well as the effects of prolonged dietary sodium deprivation on ANG II type 1 (AT1) and ANG II type 2 (AT2) receptors and angiotensin-convertion enzyme (ACE) mRNA levels in the involved brain regions using the method of real-time polymerase chain reaction (PCR). Results showed that the Fos immunoreactivity (Fos-ir) expression in forebrain areas such as subfornical organ (SFO), paraventricular hypothalamic nuclei (PVN), supraoptic nucleus (SON) and organum vasculosum laminae terminalis (OVLT) all increased significantly and that the levels of ANG I, ANG II and ALD also increased in plasma and forebrain in rats fed with low sodium diet. In contrast, AT1, ACE mRNA in PVN, SON and OVLT decreased significantly in dietary sodium depleted rats, while AT2 mRNA expression did not change in the examined areas. These results suggest that many brain areas are activated by increased levels of plasma and/or brain ANG II and ALD, which underlies the elevated preference for hypertonic salt solution after prolonged exposure to low sodium diet, and that the regional AT1 and ACE mRNA are down-regulated after dietary sodium deprivation, which may be mediated by increased ANG II in plasma and/or brain tissue.

Resveratrol prevents angiotensin II-induced hypertrophy of vascular smooth muscle cells through the transactivation of growth factor receptors.

PubMed

Hossain, Ekhtear; Anand-Srivastava, Madhu B

2017-08-01

We previously showed that augmented levels of endogenous angiotensin II (AngII) contribute to vascular smooth muscle cell (VSMC) hypertrophy through the transactivation of growth factor receptors in spontaneously hypertensive rats. Resveratrol (RV), a polyphenolic component of red wine, has also been shown to attenuate AngII-evoked VSMC hypertrophy; however, the molecular mechanism mediating this response is obscure. The present study was therefore undertaken to examine whether RV could prevent AngII-induced VSMC hypertrophy through the transactivation of growth factor receptor and associated signaling pathways. AngII treatment of VSMC enhanced the protein synthesis that was attenuated towards control levels by RV pretreatment as well as by the inhibitors of NADPH oxidase, c-Src, and growth factor receptors. Furthermore, RV pretreatment also inhibited enhanced levels of superoxide anion, NADPH oxidase activity, increased expression of NADPH oxidase subunits, and phosphorylation of c-Src, EGF-R, PDGE-R, ERK1/2, and AKT1/2. In conclusion, these results indicate that RV attenuates AngII-induced VSMC hypertrophy through the inhibition of enhanced oxidative stress and activation of c-Src, growth factor receptors, and MAPK/AKT signaling. We suggest that RV could be used as a therapeutic agent in the treatment of vascular complications associated with hypertension and hypertrophy.

Fate of angiotensin I in the toad Bufo melanostictus

PubMed Central

Ng, K. K. F.

1973-01-01

1. The effects of angiotensin I and II on the blood pressure of pithed toads and the disappearance of angiotensin I and II in the perfused organs of the toad were studied. 2. Angiotensin I was relatively inactive on the blood pressure of pithed toads; it exhibited less than 3% of the pressor activity of angiotensin II. 3. Angiotensin I was not converted to angiotensin II during passage through the lungs. There was also no evidence of net conversion during passage through the kidney and hind quarters. 4. During passage through the lungs, 33-50% of angiotensin I was removed and 25-50% was removed during passage through the hind quarters. No loss of activity was detected when angiotensin II passed through the kidneys. 5. Angiotensin II passed through the lungs and kidneys without loss but 25-50% disappeared during passage through the hind quarters. 6. The relatively low pressor activity of angiotensin I together with its lack of conversion to angiotensin II in isolated perfused organs suggest that the converting enzyme is absent in the toad, Bufo melanostictus. PMID:4357961

Down-regulation of Cyclooxygenase-2 by the Carboxyl Tail of the Angiotensin II Type 1 Receptor*

PubMed Central

Sood, Rapita; Minzel, Waleed; Rimon, Gilad; Tal, Sharon; Barki-Harrington, Liza

2014-01-01

The enzyme cyclooxygenase-2 (COX-2) plays an important role in the kidney by up-regulating the production of the vasoconstrictor hormone angiotensin II (AngII), which in turn down-regulates COX-2 expression via activation of the angiotensin II type 1 receptor (AT1) receptor. Chemical inhibition of the catalytic activity of COX-2 is a well-established strategy for treating inflammation but little is known of cellular mechanisms that dispose of the protein itself. Here we show that in addition to its indirect negative feedback on COX-2, AT1 also down-regulates the expression of the COX-2 protein via a pathway that does not involve G-protein or β-arrestin-dependent signaling. Instead, AT1 enhances the ubiquitination and subsequent degradation of the enzyme in the proteasome through elements in its cytosolic carboxyl tail (CT). We find that a mutant receptor that lacks the last 35 amino acids of its CT (Δ324) is devoid of its ability to reduce COX-2, and that expression of the CT sequence alone is sufficient to down-regulate COX-2. Collectively these results propose a new role for AT1 in regulating COX-2 expression in a mechanism that deviates from its canonical signaling pathways. Down-regulation of COX-2 by a short peptide that originates from AT1 may present as a basis for novel therapeutic means of eliminating excess COX-2 protein. PMID:25231994

Selection of a high-affinity and in vivo bioactive ssDNA aptamer against angiotensin II peptide.

PubMed

Heiat, Mohammad; Ranjbar, Reza; Latifi, Ali Mohammad; Rasaee, Mohammad Javad

2016-08-01

Unique features of aptamers have attracted interests for a broad range of applications. Aptamers are able to specifically bind to targets and inhibit their functions. This study, aimed to isolate the high affinity ssDNA aptamers against bio-regulator peptide angiotensin II (Ang II) and investigate their bioactivity in cellular and animal models. To isolate ssDNA aptamers, 12 rounds of affinity chromatography SELEX (Systematic Evolution of Ligands by EXponential enrichment) procedure were carried out. The SPR (surface plasmon resonance) and ELONA (enzyme linked oligonucleotide assay) analysis were used to determine the affinity and specificity of aptamers. The ability of selected aptamers to inhibit the proliferative effect of Ang II on human aortic vascular smooth muscle cells (HA-VSMCs) and their performance on Wistar rat urinary system and serum electrolyte levels were investigated. Two full-length aptamers (FLC112 and FLC125) with high affinity of respectively 7.52±2.44E-10 and 5.87±1.3E-9M were isolated against Ang II. The core regions of these aptamers (CRC112 and CRC125) also showed affinity of 5.33±1.15E-9 and 4.11±1.09E-9M. In vitro analysis revealed that FLC112 and FLC125 can inhibit the proliferative effect of Ang II on HA-VSMCs (P<0.05). They also significantly reduced the serum sodium level and increased the urine volume (P<0.05). The core regions of aptamers did not show high inhibitory potential against Ang II. It can be a spotlight that ssDNA aptamers have high potential for blocking Ang II. In conclusion, it appears that the researches focusing on high affinity and bioactive aptamers may lead to excellent results in blocking Ang II activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts.

PubMed

Burger, Dylan; Montezano, Augusto C; Nishigaki, Nobuhiro; He, Ying; Carter, Anthony; Touyz, Rhian M

2011-08-01

Circulating microparticles are increased in cardiovascular disease and may themselves promote oxidative stress and inflammation. Molecular mechanisms underlying their formation and signaling are unclear. We investigated the role of reactive oxygen species (ROS), Rho kinase, and lipid rafts in microparticle formation and examined their functional significance in endothelial cells (ECs). Microparticle formation from angiotensin II (Ang II)-stimulated ECs and apolipoprotein E(-/-) mice was assessed by annexin V or by CD144 staining and electron microscopy. Ang II promoted microparticle formation and increased EC O(2)(-) generation and Rho kinase activity. Ang II-stimulated effects were inhibited by irbesartan (Ang II receptor type I blocker) and fasudil (Rho kinase inhibitor). Methyl-β-cyclodextrin and nystatin, which disrupt lipid rafts/caveolae, blocked microparticle release. Functional responses, assessed in microparticle-stimulated ECs, revealed increased O(2)(-) production, enhanced vascular cell adhesion molecule/platelet-EC adhesion molecule expression, and augmented macrophage adhesion. Inhibition of epidermal growth factor receptor blocked the prooxidative and proinflammatory effects of microparticles. In vitro observations were confirmed in apolipoprotein E(-/-) mice, which displayed vascular inflammation and high levels of circulating endothelial microparticles, effects that were reduced by apocynin. We demonstrated direct actions of Ang II on endothelial microparticle release, mediated through NADPH oxidase, ROS, and Rho kinase targeted to lipid rafts. Microparticles themselves stimulated endothelial ROS formation and inflammatory responses. Our findings suggest a feedforward system whereby Ang II promotes EC injury through its own endothelial-derived microparticles.

Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury.

PubMed

Li, Tuoyi; Yu, Bing; Liu, Zhixin; Li, Jingyuan; Ma, Mingliang; Wang, Yingbao; Zhu, Mingjiang; Yin, Huiyong; Wang, Xiaofeng; Fu, Yi; Yu, Fang; Wang, Xian; Fang, Xiaohong; Sun, Jinpeng; Kong, Wei

2018-01-02

Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg 167 and Cys 289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

Differential participation of angiotensin II type 1 and 2 receptors in the regulation of cardiac cell death triggered by angiotensin II.

PubMed

Aránguiz-Urroz, Pablo; Soto, Dagoberto; Contreras, Ariel; Troncoso, Rodrigo; Chiong, Mario; Montenegro, José; Venegas, Daniel; Smolic, Christian; Ayala, Pedro; Thomas, Walter G; Lavandero, Sergio; Díaz-Araya, Guillermo

2009-05-01

The Angiotensin II (Ang II) type 1 (AT(1)R) and type 2 (AT(2)R) receptors are increased in the heart following myocardial infarction and dilated cardiomyopathy, yet their contribution at a cellular level to compensation and/or failure remains controversial. We ectopically expressed AT(1)R and AT(2)R in cultured adult rat cardiomyocytes and cardiac fibroblasts to investigate Ang II-mediated cardiomyocyte hypertrophy and cardiac cell viability. In adult rat cardiomyocytes, Ang II did not induce hypertrophy via the AT(1)R, and no effect of Ang II on cell viability was observed following AT(1)R or AT(2)R expression. In adult rat cardiac fibroblasts, Ang II stimulated cell death by apoptosis via the AT(1)R (but not the AT(2)R), which required the presence of extracellular calcium, and induced a rapid dissipation of mitochondrial membrane potential, which was significant from 8 h. We conclude that Ang II/AT(1)R triggers apoptosis in adult rat cardiac fibroblasts, which is dependent on Ca2+ influx.

Angiotensin II-aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase.

PubMed

Batenburg, Wendy W; Jansen, Pieter M; van den Bogaerdt, Antoon J; J Danser, Alexander H

2012-04-01

The aim of this study was to investigate the aldosterone-angiotensin (Ang) II interaction in human coronary microarteries (HCMAs). HCMAs, obtained from 75 heart-beating organ donors, were mounted in myographs and exposed to Ang II, either directly or following a 30-min pre-incubation with aldosterone, 17β-oestradiol, hydrocortisone, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the extracellular regulated kinase 1/2 (ERK1/2) inhibitor PD98059, the GPR30 antagonist G15, or the epidermal growth factor receptor (EGFR) antagonist AG1478. Ang II constricted HCMAs in a concentration-dependent manner. All steroids, at nanomolar levels, potentiated Ang II and G15 prevented this effect. The potentiation disappeared or was reversed into Ang II antagonism at micromolar steroid levels. NO synthase (NOS) inhibition prevented the latter antagonism in the case of 17β-oestradiol, whereas both aldosterone and 17β-oestradiol at micro- (but not nano-) molar levels induced endothelial NOS phosphorylation in human umbilical vein endothelial cells. AG1478, but not SB203580 or PD98059, abolished the Ang II-induced contraction in the presence of aldosterone or 17β-oestradiol, and none of these drugs affected Ang II alone. Steroids including aldosterone affect Ang II-induced vasoconstriction in a biphasic manner. Potentiation occurs at nanomolar steroid levels and depends on GPR30 and EGFR transactivation. At micromolar steroid levels, this potentiation either disappears (aldosterone and hydrocortisone) or is reversed into an inhibition (17β-oestradiol), and this is due to the endothelial NOS activation that occurs at such concentrations.

Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes.

PubMed

Alvin, Zikiar V; Laurence, Graham G; Coleman, Bernell R; Zhao, Aiqiu; Hajj-Moussa, Majd; Haddad, Georges E

2011-07-01

Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

Angiotensin II-induced angiotensin II type I receptor lysosomal degradation studied by fluorescence lifetime imaging microscopy

NASA Astrophysics Data System (ADS)

Li, Hewang; Yu, Peiying; Felder, Robin A.; Periasamy, Ammasi; Jose, Pedro A.

2009-02-01

Upon activation, the angiotensin (Ang) II type 1 receptor (AT1Rs) rapidly undergoes endocytosis. After a series of intracellular processes, the internalized AT1Rs recycle back to the plasma membrane or are trafficked to proteasomes or lysosomes for degradation. We recently reported that AT1Rs degrades in proteasomes upon stimulation of the D5 dopamine receptor (D5R) in human renal proximal tubule and HEK-293 cells. This is in contrast to the degradation of AT1R in lysosomes upon binding Ang II. However, the dynamic regulation of the AT1Rs in lysosomes is not well understood. Here we investigated the AT1Rs lysosomal degradation using FRET-FLIM in HEK 293 cells heterologously expressing the human AT1R tagged with EGFP as the donor fluorophore. Compared to its basal state, the lifetime of AT1Rs decreased after a 5-minute treatment with Ang II treatment and colocalized with Rab5 but not Rab7 and LAMP1. With longer Ang II treatment (30 min), the AT1Rs lifetime decreased and co-localized with Rab5, as well as Rab7 and LAMP1. The FLIM data are corroborated with morphological and biochemical co-immunoprecipitation studies. These data demonstrate that Ang II induces the internalization of AT1Rs into early sorting endosomes prior to trafficking to late endosomes and subsequent degradation in lysosomes.

Nardosinone protects H9c2 cardiac cells from angiotensin II-induced hypertrophy.

PubMed

Du, Meng; Huang, Kun; Gao, Lu; Yang, Liu; Wang, Wen-Shuo; Wang, Bo; Huang, Kai; Huang, Dan

2013-12-01

Pathological cardiac hypertrophy induced by angiotensin II (AngII) can subsequently give rise to heart failure, a leading cause of mortality. Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis, a well-known traditional Chinese medicine. In order to investigate the effects of nardosinone on AngII-induced cardiac cell hypertrophy and the related mechanisms, the myoblast cell line H9c2, derived from embryonic rat heart, was treated with nardosinone (25, 50, 100, and 200 μmol/L) or AngII (1 μmol/L). Then cell surface area and mRNA expression of classical markers of hypertrophy were detected. The related protein levels in PI3K/Akt/mTOR and MEK/ERK signaling pathways were examined by Western blotting. It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII. The mRNA expression of ANP, BNP and β-MHC was obviously elevated in AngII-treated H9c2 cells, which could be effectively blocked by nardosinone at the concentration of 100 μmol/L. Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K/Akt and MEK/ERK signaling pathways. It was suggested that the inhibitory effect of nardosinone on Ang II-induced hypertrophy in H9c2 cells might be mediated by targeting PI3K/Akt and MEK/ERK signaling pathways.

Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

PubMed

Wang, Pei; Fedoruk, Matthew N; Rupert, Jim L

2008-01-01

activity or block the action of angiotensin II, the question is relevant to the study of ergogenic agents and to the efforts to rid sports of 'doping'. This article discusses the possibility that ACE inhibitors and ARBs, by virtue of their effects on ACE or angiotensin II function, respectively, have performance-enhancing capabilities; it also reviews the data on the effects of these medications on VO2max, muscle composition and endurance capacity in patient and non-patient populations. We conclude that, while the direct evidence supporting the hypothesis that ACE-related medications are potential doping agents is not compelling, there are insufficient data on young, athletic populations to exclude the possibility, and there is ample, albeit indirect, support from genetic studies to suggest that they should be. Unfortunately, given the history of drug experimentation in athletes and the rapid appropriation of therapeutic agents into the doping arsenal, this indirect evidence, coupled with the availability of ACE-inhibiting and ACE-receptor blocking medications may be sufficiently tempting to unscrupulous competitors looking for a shortcut to the finish line.

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) III: Endogenous Inhibition of Angiotensin Converting Enzyme (ACE) Provides Protection against Cardiovascular Diseases

PubMed Central

Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

2014-01-01

ACE inhibitor drugs decrease mortality by up to one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors. Here we investigated the clinical significance of this potential endogenous ACE inhibition. ACE concentration and activity was measured in patient's serum samples (n = 151). ACE concentration was found to be in a wide range (47–288 ng/mL). ACE activity decreased with the increasing concentration of the serum albumin (HSA): ACE activity was 56±1 U/L in the presence of 2.4±0.3 mg/mL HSA, compared to 39±1 U/L in the presence of 12±1 mg/mL HSA (values are mean±SEM). Effects of the differences in ACE concentration were suppressed in human sera: patients with ACE DD genotype exhibited a 64% higher serum ACE concentration (range, 74–288 ng/mL, median, 155.2 ng/mL, n = 52) compared to patients with II genotype (range, 47–194 ng/mL, median, 94.5 ng/mL, n = 28) while the difference in ACE activities was only 32% (range, 27.3–59.8 U/L, median, 43.11 U/L, and range 15.6–55.4 U/L, median, 32.74 U/L, respectively) in the presence of 12±1 mg/mL HSA. No correlations were found between serum ACE concentration (or genotype) and cardiovascular diseases, in accordance with the proposed suppressed physiological ACE activities by HSA (concentration in the sera of these patients: 48.5±0.5 mg/mL) or other endogenous inhibitors. Main implications are that (1) physiological ACE activity can be stabilized at a low level by endogenous ACE inhibitors, such as HSA; (2) angiotensin II elimination may have a significant role in angiotensin II related pathologies. PMID:24690767

Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow.

PubMed

Emans, Tonja W; Janssen, Ben J; Pinkham, Maximilian I; Ow, Connie P C; Evans, Roger G; Joles, Jaap A; Malpas, Simon C; Krediet, C T Paul; Koeners, Maarten P

2016-11-01

Our understanding of the mechanisms underlying the role of hypoxia in the initiation and progression of renal disease remains rudimentary. We have developed a method that allows wireless measurement of renal tissue oxygen tension in unrestrained rats. This method provides stable and continuous measurements of cortical tissue oxygen tension (PO2) for more than 2 weeks and can reproducibly detect acute changes in cortical oxygenation. Exogenous angiotensin-II reduced renal cortical tissue PO2 more than equi-pressor doses of phenylephrine, probably because it reduced renal oxygen delivery more than did phenylephrine. Activation of the endogenous renin-angiotensin system in transgenic Cyp1a1Ren2 rats reduced cortical tissue PO2; in this model renal hypoxia precedes the development of structural pathology and can be reversed acutely by an angiotensin-II receptor type 1 antagonist. Angiotensin-II promotes renal hypoxia, which may in turn contribute to its pathological effects during development of chronic kidney disease. We hypothesised that both exogenous and endogenous angiotensin-II (AngII) can decrease the partial pressure of oxygen (PO2) in the renal cortex of unrestrained rats, which might in turn contribute to the progression of chronic kidney disease. Rats were instrumented with telemeters equipped with a carbon paste electrode for continuous measurement of renal cortical tissue PO2. The method reproducibly detected acute changes in cortical oxygenation induced by systemic hyperoxia and hypoxia. In conscious rats, renal cortical PO2 was dose-dependently reduced by intravenous AngII. Reductions in PO2 were significantly greater than those induced by equi-pressor doses of phenylephrine. In anaesthetised rats, renal oxygen consumption was not affected, and filtration fraction was increased only in the AngII infused animals. Oxygen delivery decreased by 50% after infusion of AngII and renal blood flow (RBF) fell by 3.3 ml min -1 . Equi-pressor infusion of

Effect of renin-angiotensin system on sodium intake.

PubMed Central

Chiaraviglio, E

1976-01-01

1. Water and saline intake was measured in rats depleted of Na by I.P. dialysis. Na intake was prevented 180 min but not 60-90 min after bilateral nephrectomy. Unilateral nephrectomy as well as ureteral ligature had no effect on Na intake. 2. Renin (3u.) injected I.P. re-established the Na appetite abolished by nephrectomy. 3. Angiotensin I (5 ng) or II (5-40 ng) injected into the 3rd ventricle, also restored the Na intake and this effect was dose-dependent. 4. The angiotensin converting-enzyme inhibitor Sq 20,881 (1 mg/kg) inhibited the effect of AI but not that of AII in restoring Na intake. 5. It is concluded that the kidneys might play a role in the regulation of Na intake through the renin-angiotensin system. PMID:1255521

Effect of endogenous angiotensin II on renal nerve activity and its cardiac baroreflex regulation.

PubMed

Dibona, G F; Jones, S Y; Sawin, L L

1998-11-01

The effects of physiologic alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity and its cardiac baroreflex regulation were studied. The effect of angiotensin II type 1 receptor blockade with intracerebroventricular losartan was examined in conscious rats consuming a low, normal, or high sodium diet that were instrumented for the simultaneous measurement of right atrial pressure and renal sympathetic nerve activity. The gain of cardiac baroreflex regulation of renal sympathetic nerve activity (% delta renal sympathetic nerve activity/mmHg mean right atrial pressure) was measured during isotonic saline volume loading. Intracerebroventricular losartan did not decrease arterial pressure but significantly decreased renal sympathetic nerve activity in low (-36+/-6%) and normal (-24+/-5%), but not in high (-2+/-3%) sodium diet rats. Compared with vehicle treatment, losartan treatment significantly increased cardiac baroreflex gain in low (-3.45+/-0.20 versus -2.89+/-0.17) and normal (-2.89+/-0.18 versus -2.54+/-0.14), but not in high (-2.27+/-0.15 versus -2.22+/-0.14) sodium diet rats. These results indicate that physiologic alterations in endogenous angiotensin II activity tonically influence basal levels of renal sympathetic nerve activity and its cardiac baroreflex regulation.

Activity of [des-Aspartyl1]-Angiotensin II in Primary Aldosteronism

PubMed Central

Carey, Robert M.; Ayers, Carlos R.; Vaughan, E. Darracott; Peach, Michael J.; Herf, Steven M.

1979-01-01

This study describes the effects of [des-Aspartyl1]-angiotensin II ([des-Asp]-AII) on blood pressure and aldosterone production in patients with primary aldosteronism due to aldosterone-producing adrenal adenoma (APA) and idiopathic adrenal hyperplasia (IHA), and in normotensive control subjects. 10 patients with primary aldosteronism, 7 with APA and 3 with IHA, and 6 normotensive control subjects were placed on a constant 150-meq sodium diet for 4 days. [des-Asp]-AII was infused for 30 min at 6, 12, and 18 pmol/kg per min. Three groups of patients were identified on the basis of aldosterone response to [des-Asp]-AII. Group I, composed of normotensive control subjects, showed incremental increases in plasma aldosterone concentration from 6±1 to 14±3 ng/100 ml (P < 0.01) with [des-Asp]-AII infusion. Group II, composed of patients with primary aldosteronism, showed incremental increases in plasma aldosterone concentration from 33±8 to 65±13 ng/100 ml (P < 0.05) with 12 pmol/kg per min of [des-Asp]-AII. Group III, also composed of patients with primary aldosteronism, showed no increase of plasma aldosterone concentration with [des-Asp]-AII. Groups I and II showed similar percentage increases in plasma aldosterone concentration (P = NS). Group III showed significantly lower aldosterone responses than group I (P < 0.01). Group II included all patients with IHA and two patients with APA. Group III included only patients with APA. The blood pressure responses to [des-Asp]-AII of subjects in group I did not differ significantly from those of groups II or III. Thus, patients with IHA and a subgroup of patients with APA showed responsiveness to [des-Asp]-AII which was limited to adrenal cortical stimulation of aldosterone biosynthesis. This suggests that adrenal responsiveness to angiotensin is a major control mechanism in some forms of primary aldosteronism. The differential adrenal responsiveness to [des-Asp]-AII in patients with APA indicates either that there are two

Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

PubMed

Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

2014-03-01

Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

Regulation of aortic extracellular matrix synthesis via noradrenergic system and angiotensin II in juvenile rats.

PubMed

Dab, Houcine; Hachani, Rafik; Dhaouadi, Nedra; Sakly, Mohsen; Hodroj, Wassim; Randon, Jacques; Bricca, Giampiero; Kacem, Kamel

2012-10-01

Extracellular matrix (ECM) synthesis regulation by sympathetic nervous system (SNS) or angiotensin II (ANG II) was widely reported, but interaction between the two systems on ECM synthesis needs further investigation. We tested implication of SNS and ANG II on ECM synthesis in juvenile rat aorta. Sympathectomy with guanethidine (50 mg/kg, subcutaneous) and blockade of the ANG II AT1 receptors (AT1R) blocker with losartan (20 mg/kg/day in drinking water) were performed alone or in combination in rats. mRNA and protein synthesis of collagen and elastin were examined by Q-RT-PCR and immunoblotting. Collagen type I and III mRNA were increased respectively by 62 and 43% after sympathectomy and decreased respectively by 31 and 60% after AT1R blockade. Combined treatment increased collagen type III by 36% but not collagen type I. The same tendency of collagen expression was observed at mRNA and protein levels after the three treatments. mRNA and protein level of elastin was decreased respectively by 63 and 39% and increased by 158 and 15% after losartan treatment. Combined treatment abrogates changes induced by single treatments. The two systems act as antagonists on ECM expression in the aorta and combined inhibition of the two systems prevents imbalance of mRNA and protein level of collagen I and elastin induced by single treatment. Combined inhibition of the two systems prevents deposit or excessive reduction of ECM and can more prevent cardiovascular disorders.

Attenuation of myocardial fibrosis with curcumin is mediated by modulating expression of angiotensin II AT1/AT2 receptors and ACE2 in rats

PubMed Central

Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Garner, Ron E; McKallip, Robert J; Zhao, Zhi-Qing

2015-01-01

Curcumin is known to improve cardiac function by balancing degradation and synthesis of collagens after myocardial infarction. This study tested the hypothesis that inhibition of myocardial fibrosis by curcumin is associated with modulating expression of angiotensin II (Ang II) receptors and angiotensin-converting enzyme 2 (ACE2). Male Sprague Dawley rats were subjected to Ang II infusion (500 ng/kg/min) using osmotic minipumps for 2 and 4 weeks, respectively, and curcumin (150 mg/kg/day) was fed by gastric gavage during Ang II infusion. Compared to the animals with Ang II infusion, curcumin significantly decreased the mean arterial blood pressure during the course of the observation. The protein level of the Ang II type 1 (AT1) receptor was reduced, and the Ang II type 2 (AT2) receptor was up-regulated, evidenced by an increased ratio of the AT2 receptor over the AT1 receptor in the curcumin group (1.2±0.02%) vs in the Ang II group (0.7±0.03%, P<0.05). These changes were coincident with less locally expressed AT1 receptor and enhanced AT2 receptor in the intracardiac vessels and intermyocardium. Along with these modulations, curcumin significantly decreased the populations of macrophages and alpha smooth muscle actin-expressing myofibroblasts, which were accompanied by reduced expression of transforming growth factor beta 1 and phosphorylated-Smad2/3. Collagen I synthesis was inhibited, and tissue fibrosis was attenuated, as demonstrated by less extensive collagen-rich fibrosis. Furthermore, curcumin increased protein level of ACE2 and enhanced its expression in the intermyocardium relative to the Ang II group. These results suggest that curcumin could be considered as an add-on therapeutic agent in the treatment of fibrosis-derived heart failure patient who is intolerant of ACE inhibitor therapy. PMID:26648693

Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

PubMed Central

Ojeda, Norma B.; Royals, Thomas P.

2013-01-01

This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg−1·min−1) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg−1·min−1) significantly attenuated these hemodynamic changes (P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats. PMID:23344570

Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor.

PubMed

Ojeda, Norma B; Royals, Thomas P; Alexander, Barbara T

2013-04-01

This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg(-1)·min(-1)) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg(-1)·min(-1)) significantly attenuated these hemodynamic changes (P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats.

Intracrine action of angiotensin II in mesangial cells: subcellular distribution of angiotensin II receptor subtypes AT1 and AT2.

PubMed

da Silva Novaes, Antônio; Ribeiro, Rosemara Silva; Pereira, Luciana Guilhermino; Borges, Fernanda Teixeira; Boim, Mirian Aparecida

2018-02-17

Biological effects of angiotensin II (AngII) such as regulation of AngII target genes may be triggered by interaction of AngII with intracellular AngII receptor types 1 and 2 (AT 1 and AT 2 ), defined as intracrine response. The aim of this study was to examine the presence of AT 1 and AT 2 receptors in nuclear membrane of human mesangial cells (HMCs) and evaluate the possible biological effects mediated by intracellular AT 1 through an intracrine mechanism. Subcellular distribution of AT 1 and AT 2 was evaluated by immunofluorescence and by western blot in isolated nuclear extract. Endogenous intracellular synthesis of AngII was stimulated by high glucose (HG). Effects of HG were analyzed in the presence of candesartan, which prevents AngII internalization. Both receptors were found in nuclear membrane. Fluorescein isothiocyanate (FITC)-labeled AngII added to isolated nuclei produced a fluorescence that was reduced in the presence of losartan or PD-123319 and quenched in the presence of both inhibitors simultaneously. HG induced overexpression of fibronectin and increased cell proliferation in the presence of candesartan, indicating an intracrine action of AngII induced by HG. Results showed the presence of nuclear receptors in HMCs that can be activated by AngII through an intracrine response independent of cytoplasmic membrane AngII receptors.

Arterial and venous endothelia display differential functional fractalkine (CX3CL1) expression by angiotensin-II.

PubMed

Rius, Cristina; Piqueras, Laura; González-Navarro, Herminia; Albertos, Fernando; Company, Chantal; López-Ginés, Concha; Ludwig, Andreas; Blanes, Jose-Ignacio; Morcillo, Esteban J; Sanz, Maria-Jesus

2013-01-01

Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX(3)CL1) was explored. Enhanced CX(3)CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 μmol/L Ang-II increased CX(3)CL1 expression, yet neutralization of CX(3)CL1 activity only significantly inhibited Ang-II-induced mononuclear cell-human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II-induced CX(3)CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX(3)CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone. These results suggest that Ang-II induces functional CX(3)CL1 expression in arterial but not in venous endothelia. Thus, targeting endothelial CX(3)CL1-mononuclear leukocyte CX(3)CR1 interactions may constitute a new therapeutic strategy in the treatment of Ang-II-associated cardiovascular diseases.

Vascular Smooth Muscle-Specific EP4 Receptor Deletion in Mice Exacerbates Angiotensin II-Induced Renal Injury.

PubMed

Thibodeau, Jean-Francois; Holterman, Chet E; He, Ying; Carter, Anthony; Cron, Gregory O; Boisvert, Naomi C; Abd-Elrahman, Khaled S; Hsu, Karolynn J; Ferguson, Stephen S G; Kennedy, Christopher R J

2016-10-20

Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs is contraindicated in hypertension, as it may reduce glomerular filtration rate (GFR) and renal blood flow. However, the identity of the specific eicosanoid and receptor underlying these effects is not known. We hypothesized that vascular smooth muscle prostaglandin E2 (PGE2) E-prostanoid 4 (EP4) receptor deletion predisposes to renal injury via unchecked vasoconstrictive actions of angiotensin II (AngII) in a hypertension model. Mice with inducible vascular smooth muscle cell (VSMC)-specific EP4 receptor deletion were generated and subjected to AngII-induced hypertension. EP4 deletion was verified by PCR of aorta and renal vessels, as well as functionally by loss of PGE2-mediated mesenteric artery relaxation. Both AngII-treated groups became similarly hypertensive, whereas albuminuria, foot process effacement, and renal hypertrophy were exacerbated in AngII-treated EP4 VSMC-/- but not in EP4 VSMC+/+ mice and were associated with glomerular scarring, tubulointerstitial injury, and reduced GFR. AngII-treated EP4 VSMC-/- mice exhibited capillary damage and reduced renal perfusion as measured by fluorescent bead microangiography and magnetic resonance imaging, respectively. NADPH oxidase 2 (Nox2) expression was significantly elevated in AngII-treated EP4 -/- mice. EP4-receptor silencing in primary VSMCs abolished PGE2 inhibition of AngII-induced Nox2 mRNA and superoxide production. These data suggest that vascular EP4 receptors buffer the actions of AngII on renal hemodynamics and oxidative injury. EP4 agonists may, therefore, protect against hypertension-associated kidney damage. Antioxid. Redox Signal. 25, 642-656.

Renal oxygen content is increased in healthy subjects after angiotensin-converting enzyme inhibition.

PubMed

Stein, Anna; Goldmeier, Silvia; Voltolini, Sarah; Setogutti, Enio; Feldman, Carlos; Figueiredo, Eduardo; Eick, Renato; Irigoyen, Maria; Rigatto, Katya

2012-07-01

The association between renal hypoxia and the development of renal injury is well established. However, no adequate method currently exists to non-invasively measure functional changes in renal oxygenation in normal and injured patients. R2* quantification was performed using renal blood oxygen level-dependent properties. Five healthy normotensive women (50 ± 5.3 years) underwent magnetic resonance imaging in a 1.5T Signa Excite HDx scanner (GE Healthcare, Waukesha, WI). A multiple fast gradient-echo sequence was used to acquire R2*/T2* images (sixteen echoes from 2.1 ms/slice to 49.6 ms/slice in a single breath hold per location). The images were post-processed to generate R2* maps for quantification. Data were recorded before and at 30 minutes after the oral administration of an angiotensin II-converting enzyme inhibitor (captopril, 25 mg). The results were compared using an ANOVA for repeated measurements (mean + standard deviation) followed by the Tukey test. ClinicalTrials.gov: NCT01545479. A significant difference (p<0.001) in renal oxygenation (R2*) was observed in the cortex and medulla before and after captopril administration: right kidney, cortex = 11.08 ± 0.56 ms, medulla = 17.21 ± 1.47 ms and cortex = 10.30 ± 0.44 ms, medulla = 16.06 ± 1.74 ms, respectively; and left kidney, cortex= 11.79 ± 1.85 ms, medulla = 17.03 ± 0.88 ms and cortex = 10.89 ± 0.91 ms, medulla = 16.43 ± 1.49 ms, respectively. This result suggests that the technique efficiently measured alterations in renal blood oxygenation after angiotensin II-converting enzyme inhibition and that it may provide a new strategy for identifying the early stages of renal disease and perhaps new therapeutic targets.

Up-regulation of angiotensin II receptors by in vitro differentiation of murine N1E-115 neuroblastoma cells.

PubMed

Reagan, L P; Ye, X H; Mir, R; DePalo, L R; Fluharty, S J

1990-12-01

In vitro differentiation of murine neuroblastoma N1E-115 cells induced by low serum (0.5%) and dimethyl sulfoxide (1.5%) increased the uptake of 45Ca2+ as well as basal and forskolin-stimulated adenylate cyclase activity. Associated with these biochemical indices of differentiation was an increase in the density of binding sites for the angiotensin II (Ang II) receptor agonist 125I-[Sar1]-Ang II and the antagonist 125I-[Sar1,Ile8]-Ang II (125I-SARILE). This up-regulation was apparent within 24 hr and was maximal at 72 hr. Other manipulations that independently increased intracellular cAMP or Ca2+ levels produced a qualitatively similar up-regulation of Ang II receptors. In vitro differentiation did not diminish the specificity of these receptors for Ang-II related peptides. Sarcosine-substituted Ang II receptor antagonists such as [Sar1,Gly8]-Ang II, [Sar1,Thr8]-Ang II, or SARILE itself competed for 125I-SARILE in a monophasic fashion, whereas the competition displayed by the agonists Ang II, angiotensin III, and Crinia-Ang II for 125I-SARILE-labeled sites was biphasic, consisting of distinct high and low affinity components. Moreover, in vitro differentiation predominantly increased the density of high affinity sites for angiotensin III and Crinia-Ang II, but the lower affinity site for Ang II, and in all three cases the majority of this increased binding was insensitive to guanine nucleotides. Collectively, these results demonstrate that the expression of Ang II receptors on neuron-like cells is regulated by the biochemical events accompanying differentiation and suggest that the biphasic nature of the binding of some angiotensin agonists may be indicative of multiple receptor subtypes.

Angiotensin-converting enzyme inhibition and novel cardiovascular risk biomarkers: results from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study.

PubMed

Cesari, Matteo; Kritchevsky, Stephen B; Atkinson, Hal H; Penninx, Brenda W; Di Bari, Mauro; Tracy, Russell P; Pahor, Marco

2009-02-01

Beneficial effects of angiotensin-converting enzyme (ACE) inhibitors seem to be mediated by mechanisms that are partly independent of blood pressure lowering. The present study evaluates effects of an ACE inhibitor (ie, fosinopril) intervention on novel cardiovascular risk factors. Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial enrolling subjects > or =55 years old with high cardiovascular disease risk profile. Biomarkers of hemostasis (ie, plasminogen activator inhibitor 1, D-dimer), inflammation (ie, C-reactive protein, interleukin-6), and endothelial function (ie, endothelin 1, vascular cell adhesion molecule 1) were measured at the baseline, at the midterm, and at end of follow-up (after 1 year) clinic visits. Paired t test analyses (after Sidak's adjustment, P < .009) were performed to compare biomarkers modifications after fosinopril/placebo interventions. Mean age of the sample (n = 290, women 43.4%) was 66.0 years old. No significant differences were reported for C-reactive protein, interleukin 6, plasminogen activator inhibitor 1, vascular cell adhesion molecule 1, and endothelin 1 levels in the comparisons between fosinopril and placebo interventions. D-dimer was the only biomarker showing a significant difference between fosinopril intervention (median 0.32 microg/mL, interquartile range 0.22-0.52 microg/mL) and placebo (median 0.29 microg/mL, interquartile range 0.20-0.47 microg/mL, P = .007) when analyses were restricted to participants with higher compliance to treatment and receiving the maximum ACE inhibitor dosage. Angiotensin-converting enzyme inhibition does not significantly modify major biomarkers of inflammation, hemostasis, and endothelial function. Further studies should confirm the possible effect of ACE inhibitors on the fibrinolysis pathway.

Prenatal Exposure to Angiotensin II Receptor Blockers and Hemodynamic Effects on the Newborn.

PubMed

Rodríguez-Castaño, MaJosé; Corredera, Araceli; Aleo, Esther; Arruza, Luis

2015-04-01

Angiotensin II receptor blockers (ARBs) are potent antihypertensive agents that block the renin angiotensin aldosterone system (RAS). Their use in pregnancy may cause malformations, oligoanuria, hypotension, and death. Hypotension is observed up to 15% of cases and is described as refractory to volume and inotropic support, although its pathophysiology is unknown. We present a case of prenatal exposure to ARBs in order to characterize the hemodynamic compromise in the newborn, help in decision-making, and guide the therapeutic approach to these patients.

S-Enantiomer of 19-Hydroxyeicosatetraenoic Acid Preferentially Protects Against Angiotensin II-Induced Cardiac Hypertrophy.

PubMed

Shoieb, Sherif M; El-Kadi, Ayman O S

2018-06-07

We have recently demonstrated that the racemic mixture of 19-hydroxyeicosatetraenoic acid (19-HETE) protects against angiotensin II (Ang II) induced cardiac hypertrophy. Therefore, the purpose of this study was to investigate whether R- or S-enantiomer of 19-HETE confers cardioprotection against Ang II-induced cellular hypertrophy in RL-14 and H9c2 cells. Both cell lines were treated with vehicle or 10 μM Ang II in the absence and presence of 20 &#[mu]M 19(R)-HETE or 19(S)-HETE for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography - mass spectrometry (LC/MS). Gene and protein expression levels were measured using real-time PCR and Western blot analysis, respectively. The results showed that both 19(R)-HETE and 19(S)-HETE significantly decreased the metabolite formation rate of midchain HETEs namely 8-, 9-, 12- and 15-HETE compared to control group while the level of 5-HETE was selectively decreased by S-enantiomer. Moreover, both 19(R)-HETE and 19(S)-HETE significantly inhibited the catalytic activity of CYP1B1 and decreased the protein expression of 5- and 12-lipoxxygenase (LOX) as well as cyclooxygenase-2 (COX-2). Notably, the decrease in 15-LOX protein expression was only mediated by 19(S)-HETE. Moreover, both enantiomers protected against Ang II-induced cellular hypertrophy as evidenced by a significant decrease in mRNA expression of β/α-myosin heavy chain ratio, ANP, IL-6 and IL-8. Our data demonstrated that S-enantiomer of 19-HETE preferentially protected against Ang II-induced cellular hypertrophy via decreasing the level of mid-chain HETEs, inhibiting catalytic activity of CYP1B1, decreasing protein expression of LOX and COX-2 enzymes and decreasing mRNA expression of IL-6 and IL-8. The American Society for Pharmacology and Experimental Therapeutics.

Prenatal Gender-Related Nicotine Exposure Increases Blood Pressure Response to Angiotensin II in Adult Offspring

PubMed Central

Xiao, DaLiao; Xu, Zhice; Huang, Xiaohui; Longo, Lawrence D.; Yang, Shumei; Zhang, Lubo

2008-01-01

Epidemiological studies suggest that maternal cigarette smoking is associated with an increased risk of elevated blood pressure (BP) in postnatal life. The present study tested the hypothesis that prenatal nicotine exposure causes an increase in BP response to angiotensin II (Ang II) in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout the gestation. BP and vascular responses to Ang II were measured in 5-month–old adult offspring. Prenatal nicotine had no effect on baseline BP but significantly increased Ang II–stimulated BP in male but not female offspring. The baroreflex sensitivity was significantly decreased in both male and female offspring. Prenatal nicotine significantly increased arterial media thickness in male but not female offspring. In male offspring, nicotine exposure significantly increased Ang II–induced contractions of aortas and mesenteric arteries. These responses were not affected by inhibition of endothelial NO synthase activity. Losartan blocked Ang II–induced contractions in both control and nicotine-treated animals. In contrast, PD123319 had no effect on Ang II–induced contractions in control but inhibited them in nicotine-treated animals. Nicotine significantly increased Ang II type 1 receptor but decreased Ang II type 2 receptor protein levels, resulting in a significant increase in the ratio of Ang II type 1 receptor/Ang II type 2 receptor in the aorta. Furthermore, the increased contractions of mesenteric arteries were mediated by increases in intracellular Ca2+ concentrations and Ca2+ sensitivity. These results suggest that prenatal nicotine exposure alters vascular function via changes in Ang II receptor–mediated signaling pathways in adult offspring in a gender-specific manner, which may lead to an increased risk of hypertension in male offspring. PMID:18259024

Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.

PubMed

Sarkar, Chandrani; Ganju, Ramesh K; Pompili, Vincent J; Chakroborty, Debanjan

2017-02-01

Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D 2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D 2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension.

PubMed

Kim, Gwi Ran; Cho, Soo-Na; Kim, Hyung-Seok; Yu, Seon Young; Choi, Sin Young; Ryu, Yuhee; Lin, Ming Quan; Jin, Li; Kee, Hae Jin; Jeong, Myung Ho

2016-11-01

Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism. Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured. Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIα (CaMKIIα), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIα and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIα. These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIα/protein kinase D1/HDAC4/GATA6 pathway.

Interleukin 22 Promotes Blood Pressure Elevation and Endothelial Dysfunction in Angiotensin II-Treated Mice.

PubMed

Ye, Jing; Ji, Qingwei; Liu, Jianfang; Liu, Ling; Huang, Ying; Shi, Ying; Shi, Lei; Wang, Menglong; Liu, Mengling; Feng, Ying; Jiang, Huimin; Xu, Yao; Wang, Zhen; Song, Junlong; Lin, Yingzhong; Wan, Jun

2017-10-03

CD4+ T helper (Th) cells, including Th1, Th2, and Th17 cells, play critical roles in angiotensin II-induced hypertension. Th22 cells, a novel subset of Th cells, take part in cardiovascular diseases by producing IL-22 (interleukin 22). This study aimed to investigate whether IL-22 is involved in hypertension. Th22 cells and IL-22 levels were detected in angiotensin II-infused mice, and the results showed that Th22 cells and IL-22 levels significantly increased. To determine the effect of Th22/IL-22 on blood pressure regulation, angiotensin II-infused mice were treated with recombinant mouse IL-22, an anti-IL-22 neutralizing monoclonal antibody, or control. Treatment with recombinant IL-22 resulted in increased blood pressure, amplified inflammatory responses, and aggravated endothelial dysfunction, whereas the anti-IL-22 neutralizing monoclonal antibody decreased blood pressure, reduced inflammatory responses, and attenuated endothelial dysfunction. To determine whether the STAT3 (signal transducer and activator of transcription 3) pathway mediates the effect of IL-22 on blood pressure regulation, the special STAT3 pathway inhibitor S31-201 was administered to mice treated with recombinant IL-22. S31-201 treatment significantly ameliorated the IL-22 effects of increased blood pressure and endothelial dysfunction. In addition, serum IL-22 levels were significantly increased in hypertensive patients compared with healthy persons. Correlation analysis showed a positive correlation between IL-22 levels and blood pressure. IL-22 amplifies the inflammatory response, induces endothelial dysfunction and promotes blood pressure elevation in angiotensin II-induced hypertensive mice. The STAT3 pathway mediates the effect of IL-22 on hypertension. Blocking IL-22 may be a novel therapeutic strategy to prevent and treat hypertension. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy.

PubMed

von Lueder, Thomas G; Wang, Bing H; Kompa, Andrew R; Huang, Li; Webb, Randy; Jordaan, Pierre; Atar, Dan; Krum, Henry

2015-01-01

Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells. One week after MI, adult male Sprague-Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (-9.8±0.5 versus -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MI-ARNi versus MI-vehicle had lower cardiac weights (P<0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II-mediated effects. LCZ696 attenuated cardiac remodeling and dysfunction after MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker. © 2014 American Heart Association, Inc.

Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart.

PubMed

Katugampola, Sidath D; Davenport, Anthony P

2002-01-01

We investigated the binding characteristics of angiotensin receptors and used this assay to determine the predominant enzyme capable of converting angiotensin I in the human left ventricle. In homogenates of human left ventricle, (125)I-[Sar(1),Ile(8)]angiotensin II bound with sub-nanomolar affinity, with a corresponding K(D) of 0.42+/-0.09 nM, a B(max) of 11.2+/-2.3 fmol.mg(-1) protein and a Hill slope of 1.04+/-0.04. The rank order of inhibitory potency of competing ligands for the (125)I-[Sar(1),Ile(8)]angiotensin II binding site was CGP42112>angiotensin II> or =angiotensin III=angiotensin I>losartan. The angiotensin type II (AT(2)) receptor predominated in the human left ventricle over the angiotensin type I (AT(1)) receptor, with an approximate AT(1)/AT(2) receptor ratio of 35:65. No specific (125)I-angiotensin IV binding sites could be detected in the human left ventricle. Using competitive radioligand binding assays, we were able to demonstrate that the chymase/cathepsin G enzyme inhibitor chymostatin was more potent than the angiotensin-converting enzyme (ACE) inhibitor captopril at inhibiting the conversion of angiotensin I in the human left ventricle. Aprotonin (an inhibitor of cathepsin G but of not chymase) had no effect on angiotensin I conversion, suggesting that the majority of the conversion was mediated by chymase. Thus, although the current therapies used for the renin-angiotensin system have focused on ACE inhibitors and AT(1) receptor antagonists, the left ventricle of the human heart expresses mainly AT(2) receptors and the tissue-specific conversion of angiotensin I occurs predominantly via chymase rather than ACE.

Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Shanqin; Zhi, Hui; Hou, Xiuyun

2011-07-08

Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. Inmore » cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that

Renin-Angiotensin System in Diabetes.

PubMed

Rein, Johannes; Bader, Michael

2017-11-17

The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Functional role of endothelial CXCL16/CXCR6-platelet-leukocyte axis in angiotensin II-associated metabolic disorders.

PubMed

Collado, Aida; Marques, Patrice; Escudero, Paula; Rius, Cristina; Domingo, Elena; Martinez-Hervás, Sergio; Real, José T; Ascaso, Juan F; Piqueras, Laura; Sanz, Maria-Jesus

2018-05-23

Angiotensin-II (Ang-II) is the main effector peptide of the renin-angiotensin system (RAS) and promotes leukocyte adhesion to the stimulated endothelium. Because RAS activation and Ang-II signaling are implicated in metabolic syndrome (MS) and abdominal aortic aneurysm (AAA), we investigated the effect of Ang-II on CXCL16 arterial expression, the underlying mechanisms, and the functional role of the CXCL16/CXCR6 axis in these cardiometabolic disorders. Results from in vitro chamber assays revealed that CXCL16 neutralization significantly inhibited mononuclear leukocyte adhesion to arterial but not to venous endothelial cells. Flow cytometry and immunofluorescence studies confirmed that Ang-II induced enhanced endothelial CXCL16 expression, which was dependent on Nox5 up-regulation and subsequent RhoA/p38-MAPK/NFκB activation. Flow cytometry analysis further showed that MS patients had higher levels of platelet activation and a higher percentage of circulating CXCR6-expressing platelets, CXCR6-expressing-platelet-bound neutrophils, monocytes and CD8+ lymphocytes than age-matched controls, leading to enhanced CXCR6/CXCL16-dependent adhesion to the dysfunctional (Ang-II- and TNFα-stimulated) arterial endothelium. Ang-II-challenged apolipoprotein E-deficient (apoE-/-) mice had a higher incidence of AAA, macrophage, CD3+ and CXCR6+ cell infiltration and neovascularization than unchallenged animals, which was accompanied by greater CCL2, CXCL16 and VEGF mRNA expression within the lesion together with elevated levels of circulating soluble CXCL16. Significant reductions in these parameters were found in animals co-treated with the AT1 receptor antagonist losartan or in apoE-/- mice lacking functional CXCR6 receptor (CXCR6GFP/GFP). CXCR6 expression on platelet-bound monocytes and CD8+ lymphocytes may constitute a new membrane-associated biomarker for adverse cardiovascular events. Moreover, pharmacological modulation of this axis may positively affect cardiovascular

Elevated pressure causes endothelial dysfunction in mouse carotid arteries by increasing local angiotensin signaling

PubMed Central

Zhao, Yingzi; Flavahan, Sheila; Leung, Susan W.; Xu, Aimin; Vanhoutte, Paul M.

2014-01-01

Experiments were performed to determine whether or not acute exposure to elevated pressure would disrupt endothelium-dependent dilatation by increasing local angiotensin II (ANG II) signaling. Vasomotor responses of mouse-isolated carotid arteries were analyzed in a pressure myograph at a control transmural pressure (PTM) of 80 mmHg. Acetylcholine-induced dilatation was reduced by endothelial denudation or by inhibition of nitric oxide synthase (NG-nitro-l-arginine methyl ester, 100 μM). Transient exposure to elevated PTM (150 mmHg, 180 min) inhibited dilatation to acetylcholine but did not affect responses to the nitric oxide donor diethylamine NONOate. Elevated PTM also increased endothelial reactive oxygen species, and the pressure-induced endothelial dysfunction was prevented by the direct antioxidant and NADPH oxidase inhibitor apocynin (100 μM). The increase in endothelial reactive oxygen species in response to elevated PTM was reduced by the ANG II type 1 receptor (AT1R) antagonists losartan (3 μM) or valsartan (1 μM). Indeed, elevated PTM caused marked expression of angiotensinogen, the precursor of ANG II. Inhibition of ANG II signaling, by blocking angiotensin-converting enzyme (1 μM perindoprilat or 10 μM captopril) or blocking AT1Rs prevented the impaired response to acetylcholine in arteries exposed to 150 mmHg but did not affect dilatation to the muscarinic agonist in arteries maintained at 80 mmHg. After the inhibition of ANG II, elevated pressure no longer impaired endothelial dilatation. In arteries treated with perindoprilat to inhibit endogenous formation of the peptide, exogenous ANG II (0.3 μM, 180 min) inhibited dilatation to acetylcholine. Therefore, elevated pressure rapidly impairs endothelium-dependent dilatation by causing ANG expression and enabling ANG II-dependent activation of AT1Rs. These processes may contribute to the pathogenesis of hypertension-induced vascular dysfunction and organ injury. PMID:25485905

Elevated pressure causes endothelial dysfunction in mouse carotid arteries by increasing local angiotensin signaling.

PubMed

Zhao, Yingzi; Flavahan, Sheila; Leung, Susan W; Xu, Aimin; Vanhoutte, Paul M; Flavahan, Nicholas A

2015-02-15

Experiments were performed to determine whether or not acute exposure to elevated pressure would disrupt endothelium-dependent dilatation by increasing local angiotensin II (ANG II) signaling. Vasomotor responses of mouse-isolated carotid arteries were analyzed in a pressure myograph at a control transmural pressure (PTM) of 80 mmHg. Acetylcholine-induced dilatation was reduced by endothelial denudation or by inhibition of nitric oxide synthase (NG-nitro-L-arginine methyl ester, 100 μM). Transient exposure to elevated PTM (150 mmHg, 180 min) inhibited dilatation to acetylcholine but did not affect responses to the nitric oxide donor diethylamine NONOate. Elevated PTM also increased endothelial reactive oxygen species, and the pressure-induced endothelial dysfunction was prevented by the direct antioxidant and NADPH oxidase inhibitor apocynin (100 μM). The increase in endothelial reactive oxygen species in response to elevated PTM was reduced by the ANG II type 1 receptor (AT1R) antagonists losartan (3 μM) or valsartan (1 μM). Indeed, elevated PTM caused marked expression of angiotensinogen, the precursor of ANG II. Inhibition of ANG II signaling, by blocking angiotensin-converting enzyme (1 μM perindoprilat or 10 μM captopril) or blocking AT1Rs prevented the impaired response to acetylcholine in arteries exposed to 150 mmHg but did not affect dilatation to the muscarinic agonist in arteries maintained at 80 mmHg. After the inhibition of ANG II, elevated pressure no longer impaired endothelial dilatation. In arteries treated with perindoprilat to inhibit endogenous formation of the peptide, exogenous ANG II (0.3 μM, 180 min) inhibited dilatation to acetylcholine. Therefore, elevated pressure rapidly impairs endothelium-dependent dilatation by causing ANG expression and enabling ANG II-dependent activation of AT1Rs. These processes may contribute to the pathogenesis of hypertension-induced vascular dysfunction and organ injury. Copyright © 2015 the American

The synthetic triterpenoid, RTA405, increases glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells

PubMed Central

Ding, Yanfeng; Stidham, Rhesa; Bumeister, Ron; Trevino, Isaac; Winters, Ali; Sprouse, Marc; Ding, Min; Ferguson, Deborah A.; Meyer, Colin J.; Wigley, W. Christian; Ma, Rong

2012-01-01

Bardoxolone methyl, a synthetic triterpenoid, improves the estimated glomerular filtration rate (GFR) in patients with chornic kidney disease and type 2 diabetes. Since the contractile activity of mesangial cells may influence glomerular filtration, we evaluated the effect of the synthetic triterpenoid RTA405 with structural similarity to bardoxolone methyl, on GFR in rats and on mesangial cell contractility in freshly isolated glomeruli. In rats, RTA 405 increased basal GFR, assessed by inulin clearance, and attenuated the angiotensin II-induced decline in GFR. RTA 405 increased the filtration fraction, but did not affect arterial blood pressure or renal plasma flow. Glomeruli from RTA 405-treated rats were resistant to angiotensin II-induced volume reduction ex vivo. In cultured mesangial cells, angiotensin II-stimulated contraction was attenuated by RTA 405, in a dose- and time-dependent fashion. Further, Nrf2 targeted gene transcription (regulates antioxidant, anti-inflammatory, and cytoprotective responses) in mesangial cells was associated with decreased basal and reduced angiotensin II-stimulated hydrogen peroxide and calcium ion levels. These mechanisms contribute to the GFR increase that occurs following treatment with RTA 405 in rats and may underlie the effect of bardoxolone methyl on the estimated GFR in patients. PMID:23235569

Big angiotensin-25: a novel glycosylated angiotensin-related peptide isolated from human urine.

PubMed

Nagata, Sayaka; Hatakeyama, Kinta; Asami, Maki; Tokashiki, Mariko; Hibino, Hajime; Nishiuchi, Yuji; Kuwasako, Kenji; Kato, Johji; Asada, Yujiro; Kitamura, Kazuo

2013-11-29

The renin-angiotensin system (RAS), including angiotensin II (Ang II), plays an important role in the regulation of blood pressure and body fluid balance. Consequently, the RAS has emerged as a key target for treatment of kidney and cardiovascular disease. In a search for bioactive peptides using an antibody against the N-terminal portion of Ang II, we identified and characterized a novel angiotensin-related peptide from human urine as a major molecular form. We named the peptide Big angiotensin-25 (Bang-25) because it consists of 25 amino acids with a glycosyl chain and added cysteine. Bang-25 is rapidly cleaved by chymase to Ang II, but is resistant to cleavage by renin. The peptide is abundant in human urine and is present in a wide range of organs and tissues. In particular, immunostaining of Bang-25 in the kidney is specifically localized to podocytes. Although the physiological function of Bang-25 remains uncertain, our findings suggest it is processed from angiotensinogen and may represent an alternative, renin-independent path for Ang II synthesis in tissue. Copyright © 2013. Published by Elsevier Inc.

Aspirin suppresses cardiac fibroblast proliferation and collagen formation through downregulation of angiotensin type 1 receptor transcription

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Xianwei, E-mail: XWang2@UAMS.edu; Lu, Jingjun; Khaidakov, Magomed

Aspirin (acetyl salicylic acid, ASA) is a common drug used for its analgesic and antipyretic effects. Recent studies show that ASA not only blocks cyclooxygenase, but also inhibits NADPH oxidase and resultant reactive oxygen species (ROS) generation, a pathway that underlies pathogenesis of several ailments, including hypertension and tissue remodeling after injury. In these disease states, angiotensin II (Ang II) activates NADPH oxidase via its type 1 receptor (AT1R) and leads to fibroblast growth and collagen synthesis. In this study, we examined if ASA would inhibit NADPH oxidase activation, upregulation of AT1R transcription, and subsequent collagen generation in mouse cardiacmore » fibroblasts challenged with Ang II. Mouse heart fibroblasts were isolated and treated with Ang II with or without ASA. As expected, Ang II induced AT1R expression, and stimulated cardiac fibroblast growth and collagen synthesis. The AT1R blocker losartan attenuated these effects of Ang II. Similarly to losartan, ASA, and its SA moiety suppressed Ang II-mediated AT1R transcription and fibroblast proliferation as well as expression of collagens and MMPs. ASA also suppressed the expression of NADPH oxidase subunits (p22{sup phox}, p47{sup phox}, p67{sup phox}, NOX2 and NOX4) and ROS generation. ASA did not affect total NF-κB p65, but inhibited its phosphorylation and activation. These observations suggest that ASA inhibits Ang II-induced NADPH oxidase expression, NF-κB activation and AT1R transcription in cardiac fibroblasts, and fibroblast proliferation and collagen expression. The critical role of NADPH oxidase activity in stimulation of AT1R transcription became apparent in experiments where ASA also inhibited AT1R transcription in cardiac fibroblasts challenged with H{sub 2}O{sub 2}. Since SA had similar effect as ASA on AT1R expression, we suggest that ASA's effect is mediated by its SA moiety. -- Highlights: ► Aspirin in therapeutic concentrations decreases mouse cardiac

Inhibition of oxytocin-induced but not angiotensin-induced rat uterine contractions following exposure to sodium sulfide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayden, L.J.; Franklin, K.J.; Roth, S.H.

1989-01-01

Low concentrations of sodium sulfide reversibly attenuate the contractile response of the isolate rat uterus to oxytocin without affecting angiotensin II responsiveness. These findings suggest that functionally important disulfide bonds in the rat uterine oxytocin receptor, but not the angiotensin receptor, are sensitive to hydrosulfide ion. Reduction of oxytocin receptors by hydrosulfide ion may be a mechanism by which low level of H{sub 2}S delay parturition in rats.

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muchir, Antoine, E-mail: a.muchir@institut-myologie.org; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY; Wu, Wei

Highlights: • Both ACE and MEK1/2 inhibition are beneficial on cardiac function in Lmna cardiomyopathy. • MEK1/2 inhibitor has beneficial effects beyond ACE inhibition for Lmna cardiomyopathy. • These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor. - Abstract: Background: Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna{sup H222P/H222P} mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitormore » has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna{sup H222P/H222P} mice and assessed if adding a MEK1/2 inhibitor would provide added benefit. Methods: Male Lmna{sup H222P/H222P} mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated. Results: Treatment of Lmna{sup H222P/H222P} mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial

PubMed Central

Slagman, Maartje C J; Waanders, Femke; Hemmelder, Marc H; Woittiez, Arend-Jan; Janssen, Wilbert M T; Lambers Heerspink, Hiddo J; Navis, Gerjan

2011-01-01

Objective To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. Design Multicentre crossover randomised controlled trial. Setting Outpatient clinics in the Netherlands. Participants 52 patients with non-diabetic nephropathy. Interventions All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na+/day) and a regular sodium diet (target 200 mmol Na+/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. Main outcome measures The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. Results Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na+/day during a low sodium diet and 184 (6) mmol Na+/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was

Moderate dietary sodium restriction added to angiotensin converting enzyme inhibition compared with dual blockade in lowering proteinuria and blood pressure: randomised controlled trial.

PubMed

Slagman, Maartje C J; Waanders, Femke; Hemmelder, Marc H; Woittiez, Arend-Jan; Janssen, Wilbert M T; Lambers Heerspink, Hiddo J; Navis, Gerjan; Laverman, Gozewijn D

2011-07-26

To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose. Multicentre crossover randomised controlled trial. Outpatient clinics in the Netherlands. 52 patients with non-diabetic nephropathy. All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label. The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure. Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the

2-METHOXYESTRADIOL REDUCES ANGIOTENSIN II-INDUCED HYPERTENSION AND RENAL DYSFUNCTION IN OVARIECTOMIZED FEMALE AND INTACT MALE MICE

PubMed Central

Pingili, Ajeeth K.; Davidge, Karen N.; Thirunavukkarasu, Shyamala; Khan, Nayaab S.; Katsurada, Akemi; Majid, Dewan S. A.; Gonzalez, Frank J.; Navar, L. Gabriel; Malik, Kafait U.

2017-01-01

cytochrome P45 1B1 protects against angiotensin II-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine if 2-methoxyestradiol ameliorates angiotensin II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1−/−, ovariectomized female, and in Cyp1b1+/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 h. 2-Methoxyestradiol reduced angiotensin II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1−/− and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1+/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice but not in Cyp1b1+/+ male mice. The G-protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1+/+ female mice. These data suggest that 2-methoxyestradiol reduces angiotensin II-induced hypertension and associated end-organ damage in intact Cyp1b1−/−, ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. PMID:28416584

Class I HDACs Regulate Angiotensin II-Dependent Cardiac Fibrosis via Fibroblasts and Circulating Fibrocytes

PubMed Central

Williams, Sarah M.; Golden-Mason, Lucy; Ferguson, Bradley S.; Douglas, Katherine B.; Cavasin, Maria A.; Demos-Davies, Kim; Yeager, Michael E.; Stenmark, Kurt R.; McKinsey, Timothy A.

2014-01-01

Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors block cardiac fibrosis in pre-clinical models of heart failure. However, which HDAC isoforms govern cardiac fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses angiotensin II (Ang II)-mediated cardiac fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and kidney failure, our results suggest broad utility for isoform-selective HDAC inhibitors as anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells. PMID:24374140

Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial nitric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells.

PubMed

Kataoka, Hiroki; Murakami, Ryuichiro; Numaguchi, Yasushi; Okumura, Kenji; Murohara, Toyoaki

2010-06-25

Decrease in endothelial nitric oxide synthase (eNOS) expression is one of the adverse outcomes of endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha) is known to decrease eNOS expression and is an important mediator of endothelial dysfunction. We hypothesized that an angiotensin II type 1 (AT1) receptor blocker would improve endothelial function via not only inhibition of the angiotensin II signaling but also inhibition of the TNF-alpha-mediated signaling. Therefore we investigated whether an AT1 receptor blocker would restore the TNF-alpha-induced decrease in eNOS expression in cultured human umbilical vein endothelial cells (HUVEC). Pretreatment of HUVEC with an antioxidant (superoxide dismutase, alpha-tocopherol) or AT1 receptor blockers (olmesartan or candesartan) restored the TNF-alpha-dependent reduction of eNOS. The AT1 receptor blocker decreased the TNF-alpha-dependent increase of 8-isoprostane. The superoxide dismutase activities in HUVEC were stable during AT1 receptor blocker treatment, and the AT1 receptor blocker did not scavenge superoxide directly. The AT1 receptor blocker also decreased TNF-alpha-induced phosphorylation of I kappaB alpha and cell death. These results suggest that AT1 receptor blockers are able to ameliorate TNF-alpha-dependent eNOS reduction or cell injury by inhibiting superoxide production or nuclear factor-kappaB activation. (c) 2010 Elsevier B.V. All rights reserved.

Renin-angiotensin system: an old player with novel functions in skeletal muscle.

PubMed

Cabello-Verrugio, Claudio; Morales, María Gabriela; Rivera, Juan Carlos; Cabrera, Daniel; Simon, Felipe

2015-05-01

Skeletal muscle is a tissue that shows the most plasticity in the body; it can change in response to physiological and pathological stimuli. Among the diseases that affect skeletal muscle are myopathy-associated fibrosis, insulin resistance, and muscle atrophy. A common factor in these pathologies is the participation of the renin-angiotensin system (RAS). This system can be functionally separated into the classical and nonclassical RAS axis. The main components of the classical RAS pathway are angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), and Ang-II receptors (AT receptors), whereas the nonclassical axis is composed of ACE2, angiotensin 1-7 [Ang (1-7)], and the Mas receptor. Hyperactivity of the classical axis in skeletal muscle has been associated with insulin resistance, atrophy, and fibrosis. In contrast, current evidence supports the action of the nonclassical RAS as a counter-regulator axis of the classical RAS pathway in skeletal muscle. In this review, we describe the mechanisms involved in the pathological effects of the classical RAS, advances in the use of pharmacological molecules to inhibit this axis, and the beneficial effects of stimulation of the nonclassical RAS pathway on insulin resistance, atrophy, and fibrosis in skeletal muscle. © 2015 Wiley Periodicals, Inc.

A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells.

PubMed

Guo, Deng-Fu; Tardif, Valerie; Ghelima, Karin; Chan, John S D; Ingelfinger, Julie R; Chen, XiangMei; Chenier, Isabelle

2004-05-14

Angiotensin II stimulates cellular hypertrophy in cultured vascular smooth muscle and renal proximal tubular cells. This effect is believed to be one of earliest morphological changes of heart and renal failure. However, the precise molecular mechanism involved in angiotensin II-induced hypertrophy is poorly understood. In the present study we report the isolation of a novel angiotensin II type 1 receptor-associated protein. It encodes a 531-amino acid protein. Its mRNA is detected in all human tissues examined but highly expressed in the human kidney, pancreas, heart, and human embryonic kidney cells as well as rat vascular smooth muscle and renal proximal tubular cells. Protein synthesis and relative cell size analyzed by flow cytometry studies indicate that overexpression of the novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in cultured rat vascular smooth muscle and renal proximal tubular cells. In contrast, the hypertrophic effects was reversed in renal proximal tubular cell lines expressing the novel gene in the antisense orientation and its dominant negative mutant, which lacks the last 101 amino acids in its carboxyl-terminal tail. The hypertrophic effects are at least in part mediated via protein kinase B activation or cyclin-dependent kinase inhibitor, p27(kip1) protein expression level in vascular smooth muscle, and renal proximal tubular cells. Moreover, angiotensin II could not stimulate cellular hypertrophy in renal proximal tubular cells expressing the novel gene in the antisense orientation and its mutant. These findings may provide new molecular mechanisms to understand hypertrophic agents such as angiotensin II-induced cellular hypertrophy.

Angiotensin-2-mediated Ca2+ signaling in the retinal pigment epithelium: role of angiotensin-receptor-associated-protein and TRPV2 channel.

PubMed

Barro-Soria, Rene; Stindl, Julia; Müller, Claudia; Foeckler, Renate; Todorov, Vladimir; Castrop, Hayo; Strauß, Olaf

2012-01-01

Angiotensin II (AngII) receptor (ATR) is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE) expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap), and transient-receptor-potential channel-V2 (TRPV2). AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE) cells by AngII results in biphasic increases in intracellular free Ca(2+)inhibited by losartan. Xestospongin C (xest C) and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca(2+)response. RPE cells from Atrap(-/-) mice showed smaller AngII-evoked Ca(2+)peak (by 22%) and loss of sustained Ca(2+)elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD) at 15 µM stimulates intracellular Ca(2+)-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor) reduced the cannabidiol-induced Ca(2+)-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca(2+)transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca(2+)transients in the RPE by releasing Ca(2+)from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca(2+)elevation.

Angiotensin-2-Mediated Ca2+ Signaling in the Retinal Pigment Epithelium: Role of Angiotensin-Receptor- Associated-Protein and TRPV2 Channel

PubMed Central

Barro-Soria, Rene; Stindl, Julia; Müller, Claudia; Foeckler, Renate; Todorov, Vladimir; Castrop, Hayo; Strauß, Olaf

2012-01-01

Angiotensin II (AngII) receptor (ATR) is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE) expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap), and transient-receptor-potential channel-V2 (TRPV2). AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE) cells by AngII results in biphasic increases in intracellular free Ca2+inhibited by losartan. Xestospongin C (xest C) and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca2+response. RPE cells from Atrap−/− mice showed smaller AngII-evoked Ca2+peak (by 22%) and loss of sustained Ca2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD) at 15 µM stimulates intracellular Ca2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor) reduced the cannabidiol-induced Ca2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca2+transients in the RPE by releasing Ca2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca2+elevation. PMID:23185387

Angiotensin II receptor blocker inhibits abnormal accumulation of advanced glycation end products and retinal damage in a rat model of type 2 diabetes.

PubMed

Sugiyama, Tetsuya; Okuno, Takashi; Fukuhara, Masayuki; Oku, Hidehiro; Ikeda, Tsunehiko; Obayashi, Hiroshi; Ohta, Mitsuhiro; Fukui, Michiaki; Hasegawa, Goji; Nakamura, Naoto

2007-09-01

The effects of an angiotensin II receptor blocker (ARB) on the accumulation of one of advanced glycation end products (AGEs), pentosidine, expression of vascular endothelial growth factor (VEGF) and retinal function were investigated in Spontaneously Diabetic Torii (SDT) rats. Candesartan, an ARB, was administered to SDT rats from 10 to 44 weeks of age and the results compared with untreated SDT rats and SD rats. Electroretinograms (ERGs) were recorded to evaluate retinal function. At 44 weeks of age, pentosidine was quantified in the vitreous, lens and plasma using high-performance liquid chromatography (HPLC). Real-time reverse transcription-PCR (RT-PCR) analysis was also performed in order to measure VEGF mRNA expression in the retina. Histological changes were examined and immunohistochemistry for pentosidine performed on the retina and retinal microvasculature. In untreated SDT rats, the amplitudes of a- and b-waves, oscillatory potentials were reduced significantly at 44 weeks of age compared with the 10-week levels, whereas they remained unchanged in SDT rats treated with candesartan. The concentration of pentosidine in the vitreous and lens did not change in treated SDT rats but increased in untreated SDT rats. Retinal VEGF mRNA expression was inhibited in treated SDT rats. Histologically, proliferative tissue was detected around the optic disc, with pentosidine being detected only in untreated SDT rats. Our findings indicate the ARB may inhibit the development of diabetic retinopathy by reducing the accumulation of pentosidine, one of AGEs and expression of VEGF in the retina.

Aldosterone acting through the central nervous system sensitizes angiotensin II-induced hypertension.

PubMed

Xue, Baojian; Zhang, Zhongming; Roncari, Camila F; Guo, Fang; Johnson, Alan Kim

2012-10-01

Previous studies have shown that preconditioning rats with a nonpressor dose of angiotensin II (Ang II) sensitizes the pressor response produced by later treatment with a higher dose of Ang II and that Ang II and aldosterone (Aldo) can modulate each other's pressor effects through actions involving the central nervous system. The current studies tested whether Aldo can cross-sensitize the pressor actions of Ang II to enhance hypertension by employing an induction-delay-expression experimental design. Male rats were implanted for telemetered blood pressure recording. During induction, subpressor doses of either subcutaneous or intracerebroventricular Aldo were delivered for 1 week. Rats were then rested for 1 week (delay) to assure that any exogenous Aldo was metabolized. After this, Ang II was given subcutaneously for 2 weeks (expression). During induction and delay, Aldo had no sustained effect on blood pressure. However, during expression, Ang II-induced hypertension was greater in the groups receiving subcutaneous or intracerebroventricular Aldo during induction in comparison with those groups receiving vehicle. Central administration of mineralocorticoid receptor antagonist blocked sensitization. Brain tissue collected at the end of delay and expression showed increased mRNA expression of several renin-angiotensin-aldosterone system components in cardiovascular-related forebrain regions of cross-sensitized rats. Cultured subfornical organ neurons preincubated with Aldo displayed greater increases in [Ca2+]i after Ang II treatment, and there was a greater Fra-like immunoreactivity present at the end of expression in cardiovascular-related forebrain structures. Taken together, these results indicate that Aldo pretreatment cross-sensitizes the development of Ang II-induced hypertension probably by mechanisms that involve the central nervous system.

Angiotensin II Inhibits the ROMK-like Small Conductance K Channel in Renal Cortical Collecting Duct during Dietary Potassium Restriction*

PubMed Central

Wei, Yuan; Zavilowitz, Beth; Satlin, Lisa M.; Wang, Wen-Hui

2010-01-01

Base-line urinary potassium secretion in the distal nephron is mediated by small conductance rat outer medullary K (ROMK)-like channels. We used the patch clamp technique applied to split-open cortical collecting ducts (CCDs) isolated from rats fed a normal potassium (NK) or low potassium (LK) diet to test the hypothesis that AngII directly inhibits ROMK channel activity. We found that AngII inhibited ROMK channel activity in LK but not NK rats in a dose-dependent manner. The AngII-induced reduction in channel activity was mediated by AT1 receptor (AT1R) binding, because pretreatment of CCDs with losartan but not PD123319 AT1 and AT2 receptor antagonists, respectively, blocked the response. Pretreatment of CCDs with U73122 and calphostin C, inhibitors of phospholipase C (PLC) and protein kinase C (PKC), respectively, abolished the AngII-induced decrease in ROMK channel activity, confirming a role of the PLC-PKC pathway in this response. Studies by others suggest that AngII stimulates an Src family protein-tyrosine kinase (PTK) via PKC-NADPH oxidase. PTK has been shown to regulate the ROMK channel. Inhibition of NADPH oxidase with diphenyliodonium abolished the inhibitory effect of AngII or the PKC activator phorbol 12-myristate 13-acetate on ROMK channels. Suppression of PTK by herbimycin A significantly attenuated the inhibitory effect of AngII on ROMK channel activity. We conclude that AngII inhibits ROMK channel activity through PKC-, NADPH oxidase-, and PTK-dependent pathways under conditions of dietary potassium restriction. PMID:17194699

Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction.

PubMed

Wei, Yuan; Zavilowitz, Beth; Satlin, Lisa M; Wang, Wen-Hui

2007-03-02

Base-line urinary potassium secretion in the distal nephron is mediated by small conductance rat outer medullary K (ROMK)-like channels. We used the patch clamp technique applied to split-open cortical collecting ducts (CCDs) isolated from rats fed a normal potassium (NK) or low potassium (LK) diet to test the hypothesis that AngII directly inhibits ROMK channel activity. We found that AngII inhibited ROMK channel activity in LK but not NK rats in a dose-dependent manner. The AngII-induced reduction in channel activity was mediated by AT1 receptor (AT1R) binding, because pretreatment of CCDs with losartan but not PD123319 AT1 and AT2 receptor antagonists, respectively, blocked the response. Pretreatment of CCDs with U73122 and calphostin C, inhibitors of phospholipase C (PLC) and protein kinase C (PKC), respectively, abolished the AngII-induced decrease in ROMK channel activity, confirming a role of the PLC-PKC pathway in this response. Studies by others suggest that AngII stimulates an Src family protein-tyrosine kinase (PTK) via PKC-NADPH oxidase. PTK has been shown to regulate the ROMK channel. Inhibition of NADPH oxidase with diphenyliodonium abolished the inhibitory effect of AngII or the PKC activator phorbol 12-myristate 13-acetate on ROMK channels. Suppression of PTK by herbimycin A significantly attenuated the inhibitory effect of AngII on ROMK channel activity. We conclude that AngII inhibits ROMK channel activity through PKC-, NADPH oxidase-, and PTK-dependent pathways under conditions of dietary potassium restriction.

Actions of circulating angiotensin II and aldosterone in the brain contributing to hypertension.

PubMed

Leenen, Frans H H

2014-08-01

In the past 1-2 decades, it has become apparent that the brain renin-angiotensin-aldosterone system (RAAS) plays a crucial role in the regulation of blood pressure (BP) by the circulating RAAS. In the brain, angiotensinergic sympatho-excitatory pathways do not contribute to acute, second-to-second regulation but play a major role in the more chronic regulation of the setpoint for sympathetic tone and BP. Increases in plasma angiotensin II (Ang II) or aldosterone and in cerebrospinal fluid [Na(+)] can directly activate these pathways and chronically further activate/maintain enhanced activity by a slow neuromodulatory pathway involving local aldosterone, mineralocorticoid receptors (MRs), epithelial sodium channels, and endogenous ouabain. Blockade of any step in this slow pathway prevents Ang II-, aldosterone-, or salt and renal injury-induced forms of hypertension. It appears that the renal and arterial actions of circulating aldosterone and Ang II act as amplifiers but are not sufficient to cause chronic hypertension if their central actions are prevented, except perhaps at high concentrations. From a clinical perspective, oral treatment with an angiotensin type 1 (AT1)-receptor blocker at high doses can cause central AT1-receptor blockade and, in humans, lower sympathetic nerve activity. Low doses of the MR blocker spironolactone appear sufficient to cause central MR blockade and a decrease in sympathetic nerve activity. Integrating the brain actions of the circulating RAAS with its direct renal and arterial actions provides a better framework to understand the role of the circulating RAAS in the pathophysiology of hypertension and heart failure and to direct therapeutic strategies. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dual ACE-inhibition and angiotensin II AT1 receptor antagonism with curcumin attenuate maladaptive cardiac repair and improve ventricular systolic function after myocardial infarctionin rat heart.

PubMed

Pang, Xue-Fen; Zhang, Li-Hui; Bai, Feng; Wang, Ning-Ping; Ijaz Shah, Ahmed; Garner, Ron; Zhao, Zhi-Qing

2015-01-05

Curcumin has been shown to improve cardiac function by reducing degradation of extracellular matrix and inhibiting synthesis of collagen after ischemia. This study tested the hypothesis that attenuation of maladaptive cardiac repair with curcumin is associated with a dual ACE-inhibition and angiotensin II AT1 receptor antagonism after myocardial infarction. Sprague-Dawley rats were subjected to 45min ischemia followed by 7 and 42 days of reperfusion, respectively. Curcumin was fed orally at a dose of 150mg/kg/day only during reperfusion. Relative to the control animals, dietary treatment with curcumin significantly reduced levels of ACE and AT1 receptor protein as determined by Western blot assay, coincident with less locally-expressed ACE and AT1 receptor in myocardium and coronary vessels as identified by immunohistochemistry. Along with this inhibition, curcumin significantly increased protein level of AT2 receptor and its expression compared with the control. As evidenced by less collagen deposition in fibrotic myocardium, curcumin also reduced the extent of collagen-rich scar and increased mass of viable myocardium detected by Masson׳s trichrome staining. Echocardiography showed that the wall thickness of the infarcted anterior septum in the curcumin group was significantly greater than that in the control group. Cardiac contractile function was improved in the curcumin treated animals as measured by fraction shortening and ejection fraction. In cultured cardiac muscle cells, curcumin inhibited oxidant-induced AT1 receptor expression and promoted cell survival. These results suggest that curcumin attenuates maladaptive cardiac repair and enhances cardiac function, primarily mediated by a dual ACE-inhibition and AT1 receptor antagonism after myocardial infarction. Copyright © 2014 Elsevier B.V. All rights reserved.

The anteroventral third ventricle region is critical for the behavioral desensitization caused by repeated injections of angiotensin II

PubMed Central

Vento, Peter J.; Daniels, Derek

2013-01-01

A single central injection of angiotensin II (AngII) potently increases water intake; however, a growing body of research suggests that repeated, acute intracerebroventricular injections of AngII cause a reduction in the dipsogenic response to subsequent AngII. This AngII-induced behavioral desensitization is specific to the effects of angiotensin and mediated by the angiotensin type-1 (AT1) receptor. The neuroanatomical substrate for this phenomenon, however, remains unknown. The anteroventral third ventricle region (AV3V) is an important site for the behavioral and physiological actions of AngII. Therefore, we hypothesized that this region also mediates the effects of repeated central AngII administration. In support of this hypothesis, we found that repeated injections of AngII into the AV3V reduced water intake stimulated by a test injection of AngII given into this region. Moreover, repeated AngII injections in the AV3V reduced water intake after AngII was injected into the lateral ventricle. These studies also demonstrate that activation of the AT1 receptor within the AV3V is required for AngII-induced behavioral desensitization because direct injection of the AT1 receptor antagonist, losartan, into the AV3V blocked the desensitizing effect of repeated AngII injections into the lateral ventricle. These findings provide additional support for a role of the AV3V in the dipsogenic actions of AngII, and suggest that this region is critical for the desensitization that occurs after acute repeated central injections of AngII. PMID:24144549

Local renin-angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy.

PubMed

Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

1999-01-01

We have reported previously that thyroid hormone activates the circulating and tissue renin-angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin-angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin-angiotensin system in Sprague-Dawley rats was fixed by chronic angiotensin II infusion (40 ng/min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0.1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0.12+/-0.03 and 0.15+/-0.03 microgram/h per liter, 126+/-5 and 130+/-5 ng/l respectively) (means+/-s.e.m.). Despite stabilization of the circulating renin-angiotensin system, thyroid hormone induced cardiac hypertrophy (5.0+/-0.5 vs 3.5+/-0.1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74+/-2 vs 48+/-2%, 6.5+/-0.8 vs 3.8+/-0.4 ng/h per g, 231+/-30 vs 149+/-2 pg/g respectively). These results indicate that the local renin-angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy.

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging.

PubMed

Rodriguez-Perez, Ana I; Borrajo, Ana; Diaz-Ruiz, Carmen; Garrido-Gil, Pablo; Labandeira-Garcia, Jose L

2016-05-24

The local renin-angiotensin system (RAS) and insulin-like growth factor 1 (IGF-1) have been involved in longevity, neurodegeneration and aging-related dopaminergic degeneration. However, it is not known whether IGF-1 and angiotensin-II (AII) activate each other. In the present study, AII, via type 1 (AT1) receptors, exacerbated neuroinflammation and dopaminergic cell death. AII, via AT1 receptors, also increased the levels of IGF-1 and IGF-1 receptors in microglial cells. IGF-1 inhibited RAS activity in dopaminergic neurons and glial cells, and also inhibited the AII-induced increase in markers of the M1 microglial phenotype. Consistent with this, IGF-1 decreased dopaminergic neuron death induced by the neurotoxin MPP+ both in the presence and in the absence of glia. Intraventricular administration of AII to young rats induced a significant increase in IGF-1 expression in the nigral region. However, aged rats showed decreased levels of IGF-1 relative to young controls, even though RAS activity is known to be enhanced in aged animals. The study findings show that IGF-1 and the local RAS interact to inhibit or activate neuroinflammation (i.e. transition from the M1 to the M2 phenotype), oxidative stress and dopaminergic degeneration. The findings also show that this mechanism is impaired in aged animals.

Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging

PubMed Central

Rodriguez-Perez, Ana I.; Borrajo, Ana; Diaz-Ruiz, Carmen; Garrido-Gil, Pablo; Labandeira-Garcia, Jose L.

2016-01-01

The local renin-angiotensin system (RAS) and insulin-like growth factor 1 (IGF-1) have been involved in longevity, neurodegeneration and aging-related dopaminergic degeneration. However, it is not known whether IGF-1 and angiotensin-II (AII) activate each other. In the present study, AII, via type 1 (AT1) receptors, exacerbated neuroinflammation and dopaminergic cell death. AII, via AT1 receptors, also increased the levels of IGF-1 and IGF-1 receptors in microglial cells. IGF-1 inhibited RAS activity in dopaminergic neurons and glial cells, and also inhibited the AII-induced increase in markers of the M1 microglial phenotype. Consistent with this, IGF-1 decreased dopaminergic neuron death induced by the neurotoxin MPP+ both in the presence and in the absence of glia. Intraventricular administration of AII to young rats induced a significant increase in IGF-1 expression in the nigral region. However, aged rats showed decreased levels of IGF-1 relative to young controls, even though RAS activity is known to be enhanced in aged animals. The study findings show that IGF-1 and the local RAS interact to inhibit or activate neuroinflammation (i.e. transition from the M1 to the M2 phenotype), oxidative stress and dopaminergic degeneration. The findings also show that this mechanism is impaired in aged animals. PMID:27167199

New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) I: Endogenous Angiotensin Converting Enzyme (ACE) Inhibition

PubMed Central

Fagyas, Miklós; Úri, Katalin; Siket, Ivetta M.; Daragó, Andrea; Boczán, Judit; Bányai, Emese; Édes, István; Papp, Zoltán; Tóth, Attila

2014-01-01

Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2±0.7 U/L at 4-fold dilution, 51.4±0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655±145 U/L, 605±42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4±2.4 U/L, n = 4, control: 26.4±0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity

The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells.

PubMed

Ding, Yanfeng; Stidham, Rhesa D; Bumeister, Ron; Trevino, Isaac; Winters, Ali; Sprouse, Marc; Ding, Min; Ferguson, Deborah A; Meyer, Colin J; Wigley, W Christian; Ma, Rong

2013-05-01

Bardoxolone methyl, a synthetic triterpenoid, improves the estimated glomerular filtration rate (GFR) in patients with chronic kidney disease and type 2 diabetes. Since the contractile activity of mesangial cells may influence glomerular filtration, we evaluated the effect of the synthetic triterpenoid RTA 405, with structural similarity to bardoxolone methyl, on GFR in rats and on mesangial cell contractility in freshly isolated glomeruli. In rats, RTA 405 increased basal GFR, assessed by inulin clearance, and attenuated the angiotensin II-induced decline in GFR. RTA 405 increased the filtration fraction, but did not affect arterial blood pressure or renal plasma flow. Glomeruli from RTA 405-treated rats were resistant to angiotensin II-induced volume reduction ex vivo. In cultured mesangial cells, angiotensin II-stimulated contraction was attenuated by RTA 405, in a dose- and time-dependent fashion. Further, Nrf2-targeted gene transcription (regulates antioxidant, anti-inflammatory, and cytoprotective responses) in mesangial cells was associated with decreased basal and reduced angiotensin II-stimulated hydrogen peroxide and calcium ion levels. These mechanisms contribute to the GFR increase that occurs following treatment with RTA 405 in rats and may underlie the effect of bardoxolone methyl on the estimated GFR in patients.

Association between angiotensin II type 1 receptor polymorphism and sudden cardiac death in myocardial infarction.

PubMed

Kruzliak, Peter; Kovacova, Gabriela; Pechanova, Olga; Balogh, Stefan

2013-01-01

The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R). A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls. The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death. This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death.

Angiotensin II type 1 and type 2 receptor-induced cell signaling.

PubMed

Akazawa, Hiroshi; Yano, Masamichi; Yabumoto, Chizuru; Kudo-Sakamoto, Yoko; Komuro, Issei

2013-01-01

The octapeptide angiotensin II (Ang II) plays a homeostatic role in the regulation of blood pressure and water and electrolyte balance, and also contributes to the progression of cardiovascular remodeling. Ang II activates Ang II type 1 (AT1) receptor and type 2 (AT2) receptor, both of which belong to the seven-transmembrane, G protein-coupled receptor family. Most of the actions of Ang II such as promotion of cellular prolifaration, hypertrophy, and fibrosis are mediated by AT1 receptor. However, in some pathological situations, AT2 receptor shows an increase in tissue expression and functions to antagonize the actions induced by AT1 receptor. Recent studies have advanced our understanding of the molecular mechanisms underlying receptor activation and signal transduction of AT1 and AT2 receptor in the cardiovascular system.

Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition.

PubMed

Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M; Chen, Shi-You; Konkalmatt, Prasad; Wang, Xiaoyan; Asico, Laureano D; Jones, John E; Yang, Yu; Sanada, Hironobu; Felder, Robin A; Eisner, Gilbert M; Weir, Matthew R; Armando, Ines; Jose, Pedro A

2016-02-01

The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure. © 2015 American Heart Association, Inc.

Combined use of drugs inhibiting the renin-angiotensin system: prescribing patterns and risk of acute kidney injury in German nursing home residents.

PubMed

Dörks, Michael; Herget-Rosenthal, Stefan; Hoffmann, Falk; Jobski, Kathrin

2018-01-01

In 2012, the European Medicines Agency reviewed the safety of dual renin-angiotensin system (RAS) blockade because of potentially increased risks for inter alia acute kidney injury (AKI). Since residents of nursing homes are particularly vulnerable to adverse drug outcomes, the aims of our study were to describe RAS-inhibiting drug use in German nursing home residents and examine the risk of AKI associated with dual RAS blockade. Based on claims data, a nested case-control study within a cohort of RAS-inhibiting drug users was conducted. Using conditional logistic regression, confounder-adjusted odds ratios (aORs) and 95% confidence intervals (CI) were obtained for the risk of AKI associated with dual RAS blockade. Subgroup analyses were performed in patients with diabetes or chronic kidney disease and both comorbidities. Of all 127,227 nursing home residents, the study cohort included 64,567 (50.7%) who were treated with at least one RAS-inhibiting drug. More than three quarters of the study population were female (77.1%). Mean age was 86.0 ± 6.8 years. Most residents were treated with angiotensin-converting enzyme inhibitors (77.8%), followed by angiotensin II receptor blockers (21.6%) and aliskiren (0.2%). Annual prevalence of dual RAS blockade declined from 9.6 (95% CI 7.8-11.8) in 2010 to 4.7 (95% CI 4.0-5.4) per 1,000 users in 2014. In the overall cohort, AKI was not significantly associated with dual RAS blockade (aOR 1.99; 0.77-5.17). However, significantly increased aORs were observed when considering patients with diabetes (3.47; 1.27-9.47), chronic kidney disease (4.74; 1.24-18.13) or both (11.17; 2.65-47.15). Prescribing of drugs inhibiting the RAS is common in German nursing homes. Though the prevalence of dual RAS blockade declined, our study showed an increased risk of AKI in patients with diabetes and/or chronic kidney disease. Therefore, cautious use is warranted in these vulnerable patients.

Comparative Effects of Angiotensin and ACTH on Cyclic AMP and Steroidogenesis in Isolated Bovine Adrenal Cells

PubMed Central

Peytremann, Andre; Nicholson, Wendell E.; Brown, Ronald D.; Liddle, Grant W.; Hardman, Joel G.

1973-01-01

The comparative effects of angiotensin II and adrenocorticotropic hormone (ACTH) on cyclic AMP and steroidogenesis were investigated employing isolated bovine adrenal cells from the zona fasciculata. Like ACTH, angiotensin produced a prompt increase in cyclic AMP which preceded the increase in corticosteroid production. Although this increase in cyclic AMP was small when compared to that induced by ACTH, it correlated with the amount of steroidogenesis. This observation is consistent with the view that cyclic AMP is the intracellular mediator of the steroidogenic action of angiotensin. Angiotensin acted synergistically with ACTH on cyclic AMP levels. This synergism was not explained by inhibition of phosphodiesterase activity. Unlike ACTH, angiotensin failed to stimulate adenylate cyclase in broken cell preparations. The observations suggest that more than one mechanism may be involved in effects of ACTH and angiotensin on cyclic AMP levels. PMID:4348344

Azilsartan, an angiotensin II type 1 receptor blocker, attenuates tert-butyl hydroperoxide-induced endothelial cell injury through inhibition of mitochondrial dysfunction and anti-inflammatory activity.

PubMed

Liu, Hao; Mao, Ping; Wang, Jia; Wang, Tuo; Xie, Chang-Hou

2016-03-01

Angiotensin II type 1 receptor (AT1-R) blockers protect against brain ischemia by mechanisms dependent on and independent of arterial blood pressure. However, the effects of AT1-R blockers on brain endothelial cell injury and detailed mechanisms remain unclear. The goal of this study is to investigate whether azilsartan, an AT1-R blocker, could attenuate oxidative injury in endothelial cells via regulating mitochondrial function and inflammatory responses. We found that treatment with azilsartan suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in murine brain endothelial cells (mBECs) by increasing cell viability, decreasing lactate dehydrogenase (LDH) release and inhibiting cell apoptosis. Azilsartan significantly inhibited reactive oxygen species (ROS) generation and lipid peroxidation, but had no effect on antioxidant system. We also detected preserved mitochondrial function after azilsartan treatment, as evidenced by increased mitochondrial membrane potential (MMP), reduced cytochrome c release, preserved ATP synthesis and inhibited mitochondrial swelling. In addition, azilsartan differently regulated expression of inflammatory cytokines and increased the activation of endothelial nitric oxide synthase (eNOS). Pretreatment with eNOS inhibitor L-NIO partially prevented the azilsartan-induced regulation of cytokines and protection. Furthermore, azilsartan-induced protection in our in vitro model was shown to be associated with protein stability of peroxisome proliferator-activated receptor-γ (PPAR-γ). Overall, our data suggest that the AT1-R blocker azilsartan may have therapeutic values in treating endothelial dysfunction associated neurological disorders through anti-oxidative and anti-inflammatory properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Non-Classical Renin-Angiotensin System and Renal Function

PubMed Central

Chappell, Mark C.

2014-01-01

The renin-angiotensin-system (RAS) constitutes one of the most important hormonal systems in the physiological regulation of blood pressure through renal and non-renal mechanisms. Indeed, dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies including kidney injury and blockade of this system by the inhibition of angiotensin converting enzyme (ACE) or blockade of the angiotensin type 1 receptor (AT1R) by selective antagonists constitutes an effective therapeutic regimen. It is now apparent with the identification of multiple components of the RAS within the kidney and other tissues that the system is actually composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS can be defined as the ACE-Ang II AT1R axis that promotes vasoconstriction, water intake, sodium retention and other mechanisms to maintain blood pressure, as well as increase oxidative stress, fibrosis, cellular growth and inflammation in pathological conditions. In contrast, the non-classical RAS composed primarily of the AngII/Ang III–AT2R pathway and the ACE2-Ang-(1-7)-AT7R axis generally opposes the actions of a stimulated Ang II-AT1R axis through an increase in nitric oxide and prostaglandins and mediates vasodilation, natriuresis, diuresis, and a reduced oxidative stress. Moreover, increasing evidence suggests that these non-classical RAS components contribute to the therapeutic blockade of the classical system to reduce blood pressure and attenuate various indices of renal injury, as well as contribute to normal renal function. PMID:23720263

Dual renin-angiotensin-aldosterone blockade: promises and pitfalls.

PubMed

Chrysant, Steven G; Chrysant, George S

2015-01-01

Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3 years will be presented in this review.

Cyanidin-3-glucoside attenuates angiotensin II-induced oxidative stress and inflammation in vascular endothelial cells.

PubMed

Sivasinprasasn, Sivanan; Pantan, Rungusa; Thummayot, Sarinthorn; Tocharus, Jiraporn; Suksamrarn, Apichart; Tocharus, Chainarong

2016-10-28

Angiotensin II (Ang II) causes oxidative stress and vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of inflammatory cardiovascular diseases such as atherosclerosis. Therefore, interventions of oxidative stress and inflammation may contribute to the reduction of cardiovascular diseases. Cyanidin-3-glucoside (C3G) plays a role in the prevention of oxidative damage in several diseases. Here, we investigated the effect of C3G on Ang II-induced oxidative stress and vascular inflammation in human endothelial cells (EA.hy926). C3G dose-dependently suppressed the free radicals and inhibited the nuclear factor-kappa B (NF-κB) signaling pathway by protecting the degradation of inhibitor of kappa B-alpha (IκB-α), inhibiting the expression and translocation of NF-κB into the nucleus through the down-regulation of NF-κB p65 and reducing the expression of inducible nitric oxide synthase (iNOS). Pretreatment with C3G not only prohibited the NF-κB signaling pathway but also promoted the activity of the nuclear erythroid-related factor 2 (Nrf2) signaling pathway through the upregulation of endogenous antioxidant enzymes. Particularly, we observed that C3G significantly enhanced the production of superoxide dismutase (SOD) and induced the expression of heme oxygenase (HO-1). Our findings confirm that C3G can protect against vascular endothelial cell inflammation induced by AngII. C3G may represent a promising dietary supplement for the prevention of inflammation, thereby decreasing the risk for the development of atherosclerosis. Copyright © 2016. Published by Elsevier Ireland Ltd.

The anteroventral third ventricle region is critical for the behavioral desensitization caused by repeated injections of angiotensin II.

PubMed

Vento, Peter J; Daniels, Derek

2014-01-01

A single central injection of angiotensin II (AngII) potently increases water intake; however, a growing body of research suggests that repeated, acute intracerebroventricular injections of AngII cause a reduction in the dipsogenic response to subsequent AngII. This AngII-induced behavioral desensitization is specific to the effects of angiotensin and mediated by the angiotensin type-1 (AT1) receptor. The neuroanatomical substrate for this phenomenon, however, remains unknown. The anteroventral third ventricle (AV3V) region is an important site for the behavioral and physiological actions of AngII. Therefore, we hypothesized that this region also mediates the effects of repeated central AngII administration. In support of this hypothesis, we found that repeated injections of AngII into the AV3V reduced water intake stimulated by a test injection of AngII given into this region. Moreover, repeated AngII injections in the AV3V reduced water intake after AngII was injected into the lateral ventricle. These studies also demonstrate that activation of the AT1 receptor within the AV3V is required for AngII-induced behavioral desensitization because direct injection of the AT1 receptor antagonist, losartan, into the AV3V blocked the desensitizing effect of repeated AngII injections into the lateral ventricle. These findings provide additional support for a role of the AV3V in the dipsogenic actions of AngII, and suggest that this region is critical for the desensitization that occurs after acute repeated central injections of AngII. Copyright © 2013 Elsevier B.V. All rights reserved.

Role of phosphatidylinositol 3-kinase in angiotensin II regulation of norepinephrine neuromodulation in brain neurons of the spontaneously hypertensive rat.

PubMed

Yang, H; Raizada, M K

1999-04-01

Chronic stimulation of norepinephrine (NE) neuromodulation by angiotensin II (Ang II) involves activation of the Ras-Raf-MAP kinase signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons. This pathway is only partially responsible for this heightened action of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In this study, we demonstrate that the MAP kinase-independent signaling pathway in the SHR neuron involves activation of PI3-kinase and protein kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY and SHR brain neurons and was accompanied by its translocation from the cytoplasmic to the nuclear compartment. Although the magnitude of stimulation by Ang II was comparable, the stimulation was more persistent in the SHR neuron compared with the WKY rat neuron. Inhibition of PI3-kinase had no significant effect in the WKY rat neuron. However, it caused a 40-50% attenuation of the Ang II-induced increase in norepinephrine transporter (NET) and tyrosine hydroxylase (TH) mRNAs and [3H]-NE uptake in the SHR neuron. In contrast, inhibition of MAP kinase completely attenuated Ang II stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it caused only a 45% decrease in the SHR neuron. However, an additive attenuation was observed when both kinases of the SHR neurons were inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR neurons. This stimulation was 30% higher and lasted longer in the SHR neuron compared with the WKY rat neuron. In conclusion, these observations demonstrate an exclusive involvement of PI3-kinase-PKB-dependent signaling pathway in a heightened NE neuromodulatory action of Ang II in the SHR neuron. Thus, this study offers an excellent potential for the development of new therapies for the treatment of centrally mediated hypertension.

Angiotensin Receptor Blocker Losartan Inhibits Spontaneous Motility of Isolated Human Ureter.

PubMed

Jankovic, Slobodan M; Stojadinovic, Dobrivoje; Stojadinovic, Miroslav; Jankovic, Snezana V; Djuric, Janko M; Stojic, Isidora; Kostic, Marina

2016-12-01

Ureteral motility is essential for elimination of intraluminal stones, and it may be adversely affected by cardiovascular drugs that a patient is taking chronically. The aim of our study was to test whether ACE inhibitors and an angiotensin receptor blocker may influence spontaneous contractions of isolated human ureter. Both phasic and tonic contractions of the isolated ureteral segments taken from 10 patients were measured as changes of the longitudinal tension or pressure recordings. Captopril, enalapril and losartan were separately added to the organ baths cumulatively. While enalapril (2.7 × 10 -7 -3.9 × 10 -4  M) and captopril (6.1 × 10 -7 -2.7 × 10 -3  M) did not affect either spontaneous activity or tone of isolated ureteral segments, losartan (2.9 × 10 -7 -4.2 × 10 -4  M) caused concentration-dependent inhibition of spontaneous contractions of the segments (50 % effective concentration (EC 50 ) = 13.46 ± 1.80 × 10 -6  M; F = 10.72, r = 0.79, p < 0.001). Due to differences in molecular mechanism of action, angiotensin receptor blocker losartan does and ACE inhibitors captopril and enalapril do not inhibit spontaneous contractions of isolated human ureter.

Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T-cell leukemia cells.

PubMed

Kozako, Tomohiro; Soeda, Shuhei; Yoshimitsu, Makoto; Arima, Naomichi; Kuroki, Ayako; Hirata, Shinya; Tanaka, Hiroaki; Imakyure, Osamu; Tone, Nanako; Honda, Shin-Ichiro; Soeda, Shinji

2016-05-01

Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

Sex Differences in the Behavioral Desensitization of Water Intake Observed After Repeated Central Injections of Angiotensin II.

PubMed

Santollo, Jessica; Volcko, K Linnea; Daniels, Derek

2018-02-01

Previous in vivo and in vitro studies demonstrate that the angiotensin type 1 receptor rapidly desensitizes after exposure to angiotensin II (AngII). Behaviorally, this likely underlies the reduced drinking observed after acute repeated central injections of AngII. To date, this phenomenon has been studied exclusively in male subjects. Because there are sex differences in the dipsogenic potency of AngII, we hypothesized that sex differences also exist in desensitization caused by AngII. As expected, when male rats were pretreated with AngII, they drank less water after a test injection of AngII than did rats pretreated with vehicle. Intact cycling female rats, however, drank similar amounts of water after AngII regardless of the pretreatment. To probe the mechanism underlying this sex difference, we tested the role of gonadal hormones in adult and developing rats. Gonadectomy in adults did not produce a male-like propensity for desensitization of water intake in female rats, nor did it produce a female-like response in male rats. To test if neonatal brain masculinization generated a male-like responsiveness, female pups were treated at birth with vehicle, testosterone propionate (TP), or dihydrotestosterone (DHT). When tested as adults, TP-treated female rats showed a male-like desensitization after repeated AngII that was not found in vehicle- or DHT-treated rats. Together, these data reveal a striking sex difference in the behavioral response to elevated AngII that is mediated by organizational effects of gonadal hormones and provide an example of one of the many ways that sex influences the renin-angiotensin-aldosterone system. Copyright © 2018 Endocrine Society.

Effects of captopril on the human foetal placental circulation: an interaction with bradykinin and angiotensin I.

PubMed Central

de Moura, R; Lopes, M A

1995-01-01

1. The mechanism underlying the foetal toxicity induced by captopril is not well understood. Since bradykinin and angiotensin II appear to be important in the regulation of the placental circulation, experiments were performed to assess the effects of captopril on the vascular actions of these peptides on the human foetal placental circulation. 2. Full-term human placentas, obtained from normal pregnancy, were perfused with a modified Tyrode solution bubbled with O2 using a pulsatile pump. The placental perfusion pressure was measured with a Statham pressure transducer and recorded continuously on a Hewlett-Packard polygraph. 3. Bradykinin (0.1, 0.3 and 1.0 nmol) injected into the placental arterial circulation produced an increase in placental perfusion pressure in all experiments. This effect of bradykinin was significantly inhibited by indomethacin (3 x 10(-7) M). 4. Captopril (10(-7) M) significantly potentiated the pressor effect of bradykinin on the human placental circulation (n = 6). This effect of captopril was reversed by indomethacin (3 x 10(-7) M). 5. Angiotensin I (n = 6) and angiotensin II (n = 6), injected into the placental arterial circulation, both produced dose-dependent increases in placental perfusion pressure. The dose-response curves to angiotensin I (n = 6) were significantly displaced to the right by captopril in a concentration-dependent manner. 6. We suggest that the toxic effects of captopril on the foetus, rather than reflecting an inhibition of angiotensin II formation, may instead be related to a potentiation of the vasoconstrictor effect of bradykinin on the foetal placental circulation, thereby reducing blood flow and causing foetal damage. The reasons for this are discussed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7669485

Role of copper transport protein Antioxidant-1 in Angiotensin II-induced hypertension: A key regulator of Extracellular SOD

PubMed Central

Ozumi, Kiyoshi; Sudhahar, Varadarajan; Kim, Ha Won; Chen, Gin-Fu; Kohno, Takashi; Finney, Lydia; Vogt, Stefan; McKinney, Ronald D.; Ushio-Fukai, Masuko; Fukai, Tohru

2012-01-01

Extracellular superoxide dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)-induced hypertension. We previously found that Ang II upregulates SOD3 expression and activity as a counter-regulatory mechanism; however, underlying mechanisms are unclear. Antioxidant-1 (Atox1) is shown to act as a copper-dependent transcription factor as well as copper chaperone for SOD3 in vitro, but its role in Ang II-induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression as well as SOD3 expression and activity in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular O2•− production, reduces endothelium-dependent vasodilation and increases vasoconstriction in mesenteric arterioles to a greater extent in Atox1−/− than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1−/− mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1 responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A which obtains copper from Atox1 as well as translocation of ATP7A to plasma membranes where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1−/− mice. In summary, Atox1 functions to prevent Ang II-induced endothelial dysfunction and hyper-contraction in resistant vessels as well as hypertension in vivo by reducing extracellular O2•− levels via increasing vascular SOD3 expression and activity. PMID:22753205

Local renin–angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy

PubMed Central

Kobori, H; Ichihara, A; Miyashita, Y; Hayashi, M; Saruta, T

2008-01-01

We have reported previously that thyroid hormone activates the circulating and tissue renin–angiotensin systems without involving the sympathetic nervous system, which contributes to cardiac hypertrophy in hyperthyroidism. This study examined whether the circulating or tissue renin–angiotensin system plays the principal role in hyperthyroidism-induced cardiac hypertrophy. The circulating renin–angiotensin system in Sprague–Dawley rats was fixed by chronic angiotensin II infusion (40 ng/ min, 28 days) via mini-osmotic pumps. Daily i.p. injection of thyroxine (0·1 mg/kg per day, 28 days) was used to mimic hyperthyroidism. Serum free tri-iodothyronine, plasma renin activity, plasma angiotensin II, cardiac renin and cardiac angiotensin II were measured with RIAs. The cardiac expression of renin mRNA was evaluated by semiquantitative reverse transcriptase-polymerase chain reaction. Plasma renin activity and plasma angiotensin II were kept constant in the angiotensin II and angiotensin II+thyroxine groups (0·12 ± 0·03 and 0·15 ± 0·03 μg/h per liter, 126 ± 5 and 130 ± 5 ng/l respectively) (means ± s.e.m.). Despite stabilization of the circulating renin–angiotensin system, thyroid hormone induced cardiac hypertrophy (5·0 ± 0·5 vs 3·5 ± 0·1 mg/g) in conjunction with the increases in cardiac expression of renin mRNA, cardiac renin and cardiac angiotensin II (74 ± 2 vs 48 ± 2%, 6·5 ± 0·8 vs 3·8 ± 0·4 ng/h per g, 231 ± 30 vs 149 ± 2 pg/g respectively). These results indicate that the local renin–angiotensin system plays the primary role in the development of hyperthyroidism-induced cardiac hypertrophy. PMID:9854175

The effect of losartan and carvedilol on vasopressor responses to adrenergic agonists and angiotensin II in the systemic circulation of Sprague Dawley rats.

PubMed

Abdulla, M H; Sattar, M A; Abdullah, N A; Khan, M A H; Anand Swarup, K R L; Johns, E J

2011-01-01

1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats. 2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10+5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose-response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined. 3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose-response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone. 4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in 'normal' rats. © 2010 Blackwell Publishing Ltd.

The Nox1/4 dual inhibitor GKT137831 or Nox4 knockdown inhibits Angiotensin-II-induced adult mouse cardiac fibroblast proliferation and migration. AT1 physically associates with Nox4

PubMed Central

Somanna, Naveen K.; Valente, Anthony J.; Krenz, Maike; Fay, William P.; Delafontaine, Patrice; Chandrasekar, Bysani

2017-01-01

Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuate Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibit CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2O2 production and CF proliferation and migration. Further, AT1 binds Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attnuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling. PMID:26445208

Endothelial AT₁ and AT₂ pathways in aortic responses to angiotensin II after stress and ethanol consumption in rats.

PubMed

Baptista, Rafaela de Fátima Ferreira; Chies, Agnaldo Bruno; Taipeiro, Elane de Fátima; Cordellini, Sandra

2014-12-01

Stress and ethanol are important cardiovascular risk factors. Their vascular and blood pressure (BP) effects were evaluated alone and in combination. Adult male Wistar rats (8-10 per group) were separated into control, ethanol (ethanol 20% in drinking water for 6 weeks), stress (restraint 1 h/d 5 d/week for 6 weeks), and ethanol/stress (in combination) groups. Systolic BP was evaluated weekly. Concentration-response curves for contractile responses to angiotensin II in the absence and the presence of losartan (AT1-blocker), PD123-319 (AT2-blocker), L-NAME (nitric oxide synthase inhibitor), or indomethacin (cyclooxygenase inhibitor) were obtained in isolated intact and endothelium-denuded aortas. Effective concentration 50% (EC50) and maximum response (MR) were compared among groups using MANOVA/Tukey tests. Stress and stress plus ethanol increased BP. Ethanol and stress, alone and in combination, did not alter angiotensin responses of intact aortas. PD123-319 decreased MR to angiotensin II in intact aortas from the ethanol and ethanol/stress groups relative to control in the presence of PD123-319. Losartan increased MR to angiotensin II in intact aortas from the stress and ethanol/stress groups relative to control in the presence of losartan. None of the protocols altered angiotensin responses of denuded aortas. Neither indomethacin nor L-NAME altered angiotensin responses of intact aortas from the experimental groups. Thus ethanol and ethanol plus stress may alter endothelial signaling via AT1-receptors, without changing systemic BP. Stress and stress plus ethanol may alter endothelial signaling via AT2-receptors, and thereby increase BP. Knowledge of such vascular changes induced by stress and/or ethanol may contribute to understanding adverse cardiovascular effects of stress and ethanol consumption in humans.

Mitogen-activated protein kinase is required for the behavioral desensitization that occurs after repeated injections of angiotensin II

PubMed Central

Vento, Peter J.; Daniels, Derek

2013-01-01

Angiotensin II (AngII) acts on central angiotensin type 1 (AT1) receptors to increase water and saline intake. Prolonged exposure to AngII in cell culture models results in a desensitization of the AT1 receptor that is thought to involve receptor internalization, and a behavioral correlate of this desensitization has been shown in rats after repeated central injections of AngII. Specifically, rats given repeated injections of AngII drink less water than controls after a subsequent test injection of AngII. Under the same conditions, however, repeated injections of AngII have no effect on AngII-induced saline intake. Given earlier studies indicating that separate intracellular signaling pathways mediate AngII-induced water and saline intake, we hypothesized that the desensitization observed in rats may be incomplete, leaving the receptor able to activate mitogen-activated protein (MAP) kinases (ERK1/2), which play a role in AngII-induced saline intake without affecting water intake. In support of this hypothesis, we found no difference in MAP kinase phosphorylation after an AngII test injection in rats given prior treatment with repeated injections of vehicle, AngII, or Sar1,Ile4,Ile8-AngII (SII), an AngII analog that activates MAP kinase without G protein coupling. In addition, we found that pretreatment with the MAP kinase inhibitor U0126 completely blocked the desensitizing effect of repeated AngII injections on water intake. Furthermore, AngII-induced water intake was reduced similarly by repeated injections of AngII or SII. The results suggest that G protein-independent signaling is sufficient to produce behavioral desensitization of the angiotensin system and that the desensitization requires MAP kinase activation. PMID:22581747

Mitogen-activated protein kinase is required for the behavioural desensitization that occurs after repeated injections of angiotensin II.

PubMed

Vento, Peter J; Daniels, Derek

2012-12-01

Angiotensin II (Ang II) acts on central angiotensin type 1 (AT(1)) receptors to increase water and saline intake. Prolonged exposure to Ang II in cell culture models results in a desensitization of the AT(1) receptor that is thought to involve receptor internalization, and a behavioural correlate of this desensitization has been shown in rats after repeated central injections of Ang II. Specifically, rats given repeated injections of Ang II drink less water than control animals after a subsequent test injection of Ang II. In the same conditions, however, repeated injections of Ang II have no effect on Ang II-induced saline intake. Given earlier studies indicating that separate intracellular signalling pathways mediate Ang II-induced water and saline intake, we hypothesized that the desensitization observed in rats may be incomplete, leaving the receptor able to activate mitogen-activated protein (MAP) kinases (ERK1/2), which play a role in Ang II-induced saline intake without affecting water intake. In support of this hypothesis, we found no difference in MAP kinase phosphorylation after an Ang II test injection in rats given prior treatment with repeated injections of vehicle, Ang II or Sar(1),Ile(4),Ile(8)-Ang II (SII), an Ang II analogue that activates MAP kinase without G protein coupling. In addition, we found that pretreatment with the MAP kinase inhibitor U0126 completely blocked the desensitizing effect of repeated Ang II injections on water intake. Furthermore, Ang II-induced water intake was reduced to a similar extent by repeated injections of Ang II or SII. The results suggest that G protein-independent signalling is sufficient to produce behavioural desensitization of the angiotensin system and that the desensitization requires MAP kinase activation.

Genotoxicity of Advanced Glycation End Products: Involvement of Oxidative Stress and of Angiotensin II Type 1 Receptors

NASA Astrophysics Data System (ADS)

Schupp, Nicole; Schinzel, Reinhard; Heidland, August; Stopper, Helga

2005-06-01

In patients with chronic renal failure, cancer incidence is increased. This may be related to an elevated level of genomic damage, which has been demonstrated by micronuclei formation as well as by comet assay analysis. Advanced glycation end products (AGEs) are markedly elevated in renal failure. In the comet assay, the model AGEs methylglyoxal- and carboxy(methyl)lysine-modified bovine serum albumin (BSA) induced significant DNA damage in colon, kidney, and liver cells. The addition of antioxidants prevented AGE-induced DNA damage, suggesting enhanced formation of reactive oxygen species (ROS). The coincubation with dimethylfumarate (DMF), an inhibitor of NF-κB translocation, reduced the genotoxic effect, thereby underscoring the key role of NF-κB in this process. One of the genes induced by NF-κB is angiotensinogen. The ensuing proteolytic activity yields angiotensin II, which evokes oxidative stress as well as proinflammatory responses. A modulator of the renin-angiotensin system (RAS), the angiotensin II (Ang II) receptor 1 antagonist, candesartan, yielded a reduction of the AGE-induced DNA damage, connecting the two signal pathways, RAS and AGE signaling. We were able to identify important participants in AGE-induced DNA damage: ROS, NF-κB, and Ang II, as well as modulators to prevent this DNA damage: antioxidants, DMF, and AT1 antagonists.

Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides.

PubMed

Saraiva, Victor Barbosa; de Souza Silva, Leandro; Ferreira-DaSilva, Claudio Teixeira; da Silva-Filho, João Luiz; Teixeira-Ferreira, André; Perales, Jonas; Souza, Mariana Conceição; Henriques, Maria das Graças; Caruso-Neves, Celso; de Sá Pinheiro, Ana Acacia

2011-02-18

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10(-7) M PD123319, an AT(2) receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10(-6) M losartan, an antagonist of the AT(1) receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10(-8) M Ang II or 10(-8) M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7) M A779. 10(-6) M dibutyryl-cAMP increased the level of infection and 10(-7) M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line.

PubMed

Miura, Shin-Ichiro; Suematsu, Yasunori; Matsuo, Yoshino; Tomita, Sayo; Nakayama, Asuka; Goto, Masaki; Arimura, Tadaaki; Kuwano, Takashi; Yahiro, Eiji; Saku, Keijiro

2016-11-01

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT 1 ) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT 1 receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT 1 receptor was greater than that of valsartan alone in an AT 1 receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT 1 receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT 1 receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT 1 receptor-induced Ald synthesis in human adrenocortical cells.

Angiotensin receptor blockers: Focus on cardiac and renal injury.

PubMed

Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Krishnamurthy, Prasanna; Suzuki, Kenji; Nakamura, Masahiko; Watanabe, Kenichi

2016-04-01

Angiotensin II, an important component of renin angiotensin system, is a potent vasopressor and its actions are mostly mediated via angiotensin II type 1 receptor (AT1R) and role of AT2R in counterbalancing the actions of AT1R stimulation are under extensive research. In addition to its physiological actions, angiotensin II plays important roles in the pathogenesis of atherosclerosis, hypertension, left ventricular hypertrophy, and heart failure. The effects of angiotensin II can be blocked by either suppressing its production by blocking angiotensin converting enzyme or by antagonizing its actions on AT1R using angiotensin II receptor blockers (ARBs). Instead of the extensive use of ARBs in the treatment of various cardiovascular diseases, proper selection of a particular ARB is crucial as the clinical condition of individual patient is different and also their economic status would play an essential role in medication compliance. Thus a critical review of the proven and promising actions of ARBs against various pathological conditions will be of great importance for the clinicians as well as for the researchers. Copyright © 2016 Elsevier Inc. All rights reserved.

C1QTNF1 attenuates angiotensin II-induced cardiac hypertrophy via activation of the AMPKa pathway.

PubMed

Wu, Leiming; Gao, Lu; Zhang, Dianhong; Yao, Rui; Huang, Zhen; Du, Binbin; Wang, Zheng; Xiao, Lili; Li, Pengcheng; Li, Yapeng; Liang, Cui; Zhang, Yanzhou

2018-06-01

Complement C1q tumor necrosis factor related proteins (C1QTNFs) have been reported to have diverse biological influence on the cardiovascular system. C1QTNF1 is a member of the CTRP superfamily. C1QTNF1 is expressed in the myocardium; however, its function in myocytes has not yet been investigated. To systematically investigate the roles of C1QTNF1 in angiotensin II (Ang II)-induced cardiac hypertrophy. C1QTNF1 knock-out mice were used with the aim of determining the role of C1QTNF1 in cardiac hypertrophy in the adult heart. Data from experiments showed that C1QTNF1 was up-regulated during cardiac hypertrophic processes, which were triggered by increased reactive oxygen species. C1QTNF1 deficiency accelerated cardiac hypertrophy, fibrosis, inflammation responses, and oxidative stress with deteriorating cardiac dysfunction in the Ang II-induced cardiac hypertrophy mouse model. We identified C1QTNF1 as a negative regulator of cardiomyocyte hypertrophy in Ang II-stimulated neonatal rat cardiomyocytes using the recombinant human globular domain of C1QTNF1 and C1QTNF1 siRNA. Injection of the recombinant human globular domain of C1QTNF1 also suppressed the Ang II-induced cardiac hypertrophic response in vivo. The anti-hypertrophic effects of C1QTNF1 rely on AMPKa activation, which inhibits mTOR P70S6K phosphorylation. An AMPKa inhibitor abrogated the anti-hypertrophic effects of the recombinant human globular domain of C1QTNF1 both in vivo and vitro. Moreover, C1QTNF1-mediated AMPKa activation was triggered by the inhibition of PDE1-4, which subsequently activated the cAMP/PKA/LKB1 pathway. Our results demonstrated that C1QTNF1 improves cardiac function and inhibits cardiac hypertrophy and fibrosis by increasing and activating AMPKa, suggesting that C1QTNF1 could be a therapeutic target for cardiac hypertrophy and heart failure. Copyright © 2018 Elsevier Inc. All rights reserved.

ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage.

PubMed

Sato, Teruki; Sato, Chitose; Kadowaki, Ayumi; Watanabe, Hiroyuki; Ho, Lena; Ishida, Junji; Yamaguchi, Tomokazu; Kimura, Akinori; Fukamizu, Akiyoshi; Penninger, Josef M; Reversade, Bruno; Ito, Hiroshi; Imai, Yumiko; Kuba, Keiji

2017-06-01

Elabela/Toddler/Apela (ELA) has been identified as a novel endogenous peptide ligand for APJ/Apelin receptor/Aplnr. ELA plays a crucial role in early cardiac development of zebrafish as well as in maintenance of self-renewal of human embryonic stem cells. Apelin was the first identified APJ ligand, and exerts positive inotropic heart effects and regulates the renin-angiotensin system. The aim of this study was to investigate the biological effects of ELA in the cardiovascular system. Continuous infusion of ELA peptide significantly suppressed pressure overload-induced cardiac hypertrophy, fibrosis and impaired contractility in mice. ELA treatment reduced mRNA expression levels of genes associated with heart failure and fibrosis. The cardioprotective effects of ELA were diminished in APJ knockout mice, indicating that APJ is the key receptor for ELA in the adult heart. Mechanistically, ELA downregulated angiotensin-converting enzyme (ACE) expression in the stressed hearts, whereas it showed little effects on angiotensin-converting enzyme 2 (ACE2) expression, which are distinct from the effects of Apelin. FoxM1 transcription factor, which induces ACE expression in the stressed hearts, was downregulated by ELA but not by Apelin. ELA antagonized angiotensin II-induced hypertension, cardiac hypertrophy, and fibrosis in mice. The ELA-APJ axis protects from pressure overload-induced heart failure possibly via suppression of ACE expression and pathogenic angiotensin II signalling. The different effects of ELA and Apelin on the expression of ACE and ACE2 implicate fine-tuned mechanisms for a ligand-induced APJ activation and downstream signalling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Albuminuria enhances NHE3 and NCC via stimulation of mitochondrial oxidative stress/angiotensin II axis.

PubMed

Jia, Zhanjun; Zhuang, Yibo; Hu, Caiyu; Zhang, Xintong; Ding, Guixia; Zhang, Yue; Rohatgi, Rajeev; Hua, Hu; Huang, Songming; He, John Ci-Jiang; Zhang, Aihua

2016-07-26

Imbalance of salt and water is a frequent and challenging complication of kidney disease, whose pathogenic mechanisms remain elusive. Employing an albumin overload mouse model, we discovered that albuminuria enhanced the expression of NHE3 and NCC but not other transporters in murine kidney in line with the stimulation of angiotensinogen (AGT)/angiotensin converting enzyme (ACE)/angiotensin (Ang) II cascade. In primary cultures of renal tubular cells, albumin directly stimulated AGT/ACE/Ang II and upregulated NHE3 and NCC expression. Blocking Ang II production with an ACE inhibitor normalized the upregulation of NHE3 and NCC in cells. Interestingly, albumin overload significantly reduced mitochondrial superoxide dismutase (SOD2), and administration of a SOD2 mimic (MnTBAP) normalized the expression of NHE3, NCC, and the components of AGT/ACE pathway affected by albuminuria, indicating a key role of mitochondria-derived oxidative stress in modulating renin-angiotensin system (RAS) and renal sodium transporters. In addition, the functional data showing the reduced urinary excretion of Na and Cl and enhanced response to specific NCC inhibitor further supported the regulatory results of sodium transporters following albumin overload. More importantly, the upregulation of NHE3 and NCC and activation of ACE/Ang II signaling pathway were also observed in albuminuric patient kidneys, suggesting that our animal model accurately replicates the human condition. Taken together, these novel findings demonstrated that albuminuria is of importance in resetting renal salt handling via mitochondrial oxidative stress-initiated stimulation of ACE/Ang II cascade. This may also offer novel, effective therapeutic targets for dealing with salt and water imbalance in proteinuric renal diseases.

ANO1 contributes to angiotensin-II-activated Ca2+-dependent Cl- current in human atrial fibroblasts.

PubMed

El Chemaly, Antoun; Norez, Caroline; Magaud, Christophe; Bescond, Jocelyn; Chatelier, Aurelien; Fares, Nassim; Findlay, Ian; Jayle, Christophe; Becq, Frederic; Faivre, Jean-François; Bois, Patrick

2014-03-01

Cardiac fibroblasts are an integral part of the myocardial tissue and contribute to its remodelling. This study characterises for the first time the calcium-dependent chloride channels (CaCC) in the plasma membrane of primary human atrial cardiac fibroblasts by means of the iodide efflux and the patch clamp methods. The calcium ionophore A23187 and Angiotensin II (Ang II) activate a chloride conductance in cardiac fibroblasts that shares pharmacological similarities with calcium-dependent chloride channels. This chloride conductance is depressed by RNAi-mediated selective Anoctamine 1 (ANO1) but not by Anoctamine 2 (ANO2) which has been revealed as CaCC and is inhibited by the selective ANO1 inhibitor, T16inh-A01. The effect of Ang II on anion efflux is mediated through AT1 receptors (with an EC50 = 13.8 ± 1.3 nM). The decrease of anion efflux by calphostin C and bisindolylmaleimide I (BIM I) suggests that chloride conductance activation is dependent on PKC. We conclude that ANO1 contributes to CaCC current in human cardiac fibroblasts and that this is regulated by Ang II acting via the AT1 receptor pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

ANGIOTENSIN CONVERTING ENZYME INHIBITION AND NOVEL CARDIOVASCULAR RISK BIOMARKERS

PubMed Central

Cesari, Matteo; Kritchevsky, Stephen B.; Atkinson, Hal H.; Penninx, Brenda W.; Di Bari, Mauro; Tracy, Russell P.; Pahor, Marco

2015-01-01

Background Beneficial effects of angiotensin converting enzyme (ACE) inhibitors seem to be mediated by mechanisms that are partly independent of blood pressure lowering. The present study evaluates effects of an ACE-inhibitor (i.e. fosinopril) intervention on novel cardiovascular risk factors. Methods Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN), a double-blind, crossover, randomized, placebo-controlled trial enrolling subjects aged ≥55 years and older with high cardiovascular disease risk profile. Biomarkers of hemostasis (i.e. plasminogen activator inhibitor-1 [PAI-1], D-dimer), inflammation (i.e. C-reactive protein [CRP], interleukin-6 [IL-6]), and endothelial function (i.e. endothelin-1, vascular cell adhesion molecule-1 [VCAM-1]) were measured at the baseline, at the mid-term, and at end of follow-up (after one year) clinic visits. Paired t-test analyses (after Sidak’s adjustment, p value<0.009) were performed to compare biomarkers modifications after fosinopril/placebo interventions. Results Mean age of the sample (n=290, women 43.4%) was 66.0 years old. No significant differences were reported for CRP, IL-6, PAI-1, VCAM-1, and endothelin-1 levels in the comparisons between fosinopril and placebo interventions. D-Dimer was the only biomarker showing a significant difference between fosinopril intervention (median 0.32 [interquartile range, IQR 0.22–0.52] µg/mL) and placebo (median 0.29 [IQR 0.20–0.47] µg/mL, p=0.007) when analyses were restricted to participants with higher compliance to treatment and receiving the maximum ACE-inhibitor dosage. Conclusions ACE-inhibition does not significantly modify major biomarkers of inflammation, hemostasis, and endothelial function. Further studies should confirm the possible effect of ACE-inhibitors on the fibrinolysis pathway. PMID:19185642

Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats.

PubMed

Motawi, Tarek K; El-Maraghy, Shohda A; Senousy, Mahmoud A

2013-07-01

Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor-β1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs. © 2013 Wiley Periodicals, Inc.

The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

PubMed

Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-07-15

The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Does inhibition of angiotensin function cause neuroprotection in diffuse traumatic brain injury?

PubMed

Khaksari, Mohammad; Rajizadeh, Mohammad Amin; Bejeshk, Mohammad Abbas; Soltani, Zahra; Motamedi, Sina; Moramdi, Fatemeh; Islami, Masoud; Shafa, Shahriyar; Khosravi, Sepehr

2018-06-01

Neuroprotection is created following the inhibition of angiotensin II type 1 receptor (AT1R). Therefore, the purpose of this research was examining AT1R blockage by candesartan in diffuse traumatic brain injury (TBI). Male rats were assigned into sham, TBI, vehicle, and candesartan groups. Candesartan (0.3 mg/kg) or vehicle was administered IP, 30 min post-TBI. Brain water and Evans blue contents were determined, 24 and 5 hr after TBI, respectively. Intracranial pressure (ICP) and neurologic outcome were evaluated at -1, 1, 4 and 24 hr after TBI. Oxidant index [malondialdehyde (MDA)] was determined 24 hr after TBI. Brain water and Evans blue contents, and MDA and ICP levels increased in TBI and vehicle groups in comparison with the sham group. Candesartan attenuated the TBI-induced brain water and Evans blue contents, and ICP and MDA enhancement. The neurologic score enhanced following candesartan administration, 24 hr after TBI. The blockage of AT1R may be neuroprotective by decreasing ICP associated with the reduction of lipid peroxidation, brain edema, and blood-brain barrier (BBB) permeability, which led to the improvement of neurologic outcome.

Angiotensin II or epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats

PubMed Central

Kimura, Debora Conte; Nagaoka, Marcia Regina; Borges, Durval Rosa; Kouyoumdjian, Maria

2017-01-01

AIM To study hepatic vasoconstriction and glucose release induced by angiotensin (Ang)II or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat (SHR). METHODS Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngII or epinephrine (Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS The portal hypertensive response (PHR) and the glucose release induced by AngII of L-NAME were similar to normal rats (WIS). On the other hand, the PHR induced by Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngII was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION AngII and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngII; the diminished glucose release induced by AngII in SHR is not related to glycogen content. PMID:28660012

Angiotensin II promotes differentiation of mouse c-kit-positive cardiac stem cells into pacemaker-like cells

PubMed Central

XUE, CHENG; ZHANG, JUN; LV, ZHAN; LIU, HUI; HUANG, CONGXIN; YANG, JING; WANG, TEN

2015-01-01

Cardiac stem cells (CSCs) can differentiate into cardiac muscle-like cells; however, it remains unknown whether CSCs may possess the ability to differentiate into pacemaker cells. The aim of the present study was to determine whether angiotensin II (Ang II) could promote the specialization of CSCs into pacemaker-like cells. Mouse CSCs were treated with Ang II from day 3–5, after cell sorting. The differentiation potential of the cells was then analyzed by morphological analysis, flow cytometry, reverse transcription-polymerase chain reaction, immunohistochemistry and patch clamp analysis. Treatment with Ang II resulted in an increased number of cardiac muscle-like cells (32.7±4.8% vs. 21.5±4.8%; P<0.05), and inhibition of smooth muscle-like cells (6.2±7.3% vs. 20.5±5.1%; P<0.05). Following treatment with Ang II, increased levels of the cardiac progenitor-specific markers GATA4 and Nkx2.5 were observed in the cells. Furthermore, the transcript levels of pacemaker function-related genes, including hyperpolarization-activated cyclic nucleotide-gated (HCN)2, HCN4, T-box (Tbx)2 and Tbx3, were significantly upregulated. Immunofluorescence analysis confirmed the increased number of pacemaker-like cells. The pacemaker current (If) was recorded in the cells derived from CSCs, treated with Ang II. In conclusion, treatment of CSCs with Ang II during the differentiation process modified cardiac-specific gene expression and resulted in the enhanced formation of pacemaker-like cells. PMID:25572000

Angiotensin II Reduces Food Intake by Altering Orexigenic Neuropeptide Expression in the Mouse Hypothalamus

PubMed Central

Yoshida, Tadashi; Semprun-Prieto, Laura; Wainford, Richard D.; Sukhanov, Sergiy; Kapusta, Daniel R.

2012-01-01

Angiotensin II (Ang II), which is elevated in many chronic disease states such as end-stage renal disease and congestive heart failure, induces cachexia and skeletal muscle wasting by increasing muscle protein breakdown and reducing food intake. Neurohormonal mechanisms that mediate Ang II-induced appetite suppression are unknown. Consequently, we examined the effect of Ang II on expression of genes regulating appetite. Systemic Ang II (1 μg/kg · min) infusion in FVB mice rapidly reduced hypothalamic expression of neuropeptide Y (Npy) and orexin and decreased food intake at 6 h compared with sham-infused controls but did not change peripheral leptin, ghrelin, adiponectin, glucagon-like peptide, peptide YY, or cholecystokinin levels. These effects were completely blocked by the Ang II type I receptor antagonist candesartan or deletion of Ang II type 1a receptor. Ang II markedly reduced phosphorylation of AMP-activated protein kinase (AMPK), an enzyme that is known to regulate Npy expression. Intracerebroventricular Ang II infusion (50 ng/kg · min) caused a reduction of food intake, and Ang II dose dependently reduced Npy and orexin expression in the hypothalamus cultured ex vivo. The reduction of Npy and orexin in hypothalamic cultures was completely prevented by candesartan or the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside. Thus, Ang II type 1a receptor-dependent Ang II signaling reduces food intake by suppressing the hypothalamic expression of Npy and orexin, likely via AMPK dephosphorylation. These findings have major implications for understanding mechanisms of cachexia in chronic disease states such as congestive heart failure and end-stage renal disease, in which the renin-angiotensin system is activated. PMID:22234465

Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat

PubMed Central

Yang, Xiaocun; Wang, Ying; Yan, Shuxun; Sun, Lina; Yang, Guojie; Li, Yuan; Yu, Chaonan

2017-01-01

ABSTRACT The objective is to explore the effect of testosterone on the proliferation and collagen synthesis of neonatal rat cardiac fibroblasts (CF) induced by Angiotensin II (Ang II) and the underlying mechanisms. Derived from neonatal rats, the CFs were divided into 4 groups: the control group, Ang II group, testosterone group, and testosterone + Ang II group in vitro. Cell cycle distribution, collagen counts, and phosphorylated extracellular signal-regulated kinase (ERK1/2) (p - ERK1/2) expression were assessed by flow cytometry, VG staining, and immunocytochemistry, respectively. The Ang II group had a much higher proportion of cells in the S-phase, higher collagen contents, and a higher p - ERK1/2 expression level than either the control or testosterone group. However, these factors were significantly reduced in the testosterone + Ang II group as compared to the Ang II group. In terms of cells in the S-phase and the collagen contents, there was not a significant difference between the testosterone group and the control. However, the protein expression of p-ERK1/2 was significantly increased in the testosterone group as compared to the control. Testosterone inhibits the proliferation and collagen synthesis of CF induced by Ang II. The underlying mechanism may involve the ERK1/2 signaling pathway. PMID:27791460

Angiotensin II induces nephrin dephosphorylation and podocyte injury: Role of caveolin-1

PubMed Central

Ren, Zhilong; Liang, Wei; Chen, Cheng; Yang, Hongxia; Singhal, Pravin C.; Ding, Guohua

2011-01-01

Nephrin, an important structural and signal molecule of podocyte slit-diaphragm (SD), has been suggested to contribute to the angiotensin II (Ang II)-induced podocyte injury. Caveolin-1 has been demonstrated to play a crucial role in signaling transduction. In the present study, we evaluated the role of caveolin-1 in Ang II-induced nephrin phosphorylation in podocytes. Wistar rats-receiving either Ang II (400 ng/kg/min) or normal saline (via subcutaneous osmotic mini-pumps, control) were administered either vehicle or telmisartan (3 mg/kg/min) for 14 or 28 days. Blood pressure, 24-hour urinary albumin and serum biochemical profile were measured at the end of the experimental period. Renal histomorphology was evaluated through light and electron microscopy. In vitro, cultured murine podocytes were exposed to Ang II (10−6 M) pretreated with or without losartan (10−5 M) for variable time periods. Nephrin and caveolin-1 expression and their phosphorylation were analyzed by Western-blotting and immunofluorescence. Caveolar membrane fractions were isolated by sucrose density gradient centrifugation, and then the distribution and interactions between Ang II type 1 receptor (AT1), nephrin, C-terminal Src kinase (Csk) and caveolin-1 were evaluated using Western-blotting and co-immunoprecipitation. Podocyte apoptosis was evaluated by cell nucleus staining with Hoechst-33342. Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. Under control conditions, podocyte displayed expression of caveolin-1 in abundance but only a low level of phospho moiety. Nonetheless, Ang II stimulated caveolin-1 phosphorylation without any change in total protein expression. Nephrin and caveolin-1 were co-localized in caveolae fractions. AT1 receptors and Csk were moved to caveolae fractions and had an interaction with caveolin-1 after the stimulation with Ang II. Transfection of caveolin-1

Angiotensin II induces apoptosis in intestinal epithelial cells through the AT2 receptor, GATA-6 and the Bax pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Lihua; Wang, Wensheng; Xiao, Weidong

2012-08-10

Highlights: Black-Right-Pointing-Pointer Ang II-induced apoptosis in intestinal epithelial cell through AT2 receptor. Black-Right-Pointing-Pointer The apoptosis process involves in the Bax/Bcl-2 intrinsic pathway. Black-Right-Pointing-Pointer GATA-6 short hairpin RNA reduced Bax expression, but not Bcl-2. Black-Right-Pointing-Pointer GATA-6 may play a critical role in apoptosis in response to the Ang II challenge. -- Abstract: Angiotensin II (Ang II) has been shown to play an important role in cell apoptosis. However, the mechanisms of Ang-II-induced apoptosis in intestinal epithelial cells are not fully understood. GATA-6 is a zinc finger transcription factor expressed in the colorectal epithelium, which directs cell proliferation, differentiation and apoptosis. Inmore » the present study we investigated the underlying mechanism of which GATA-6 affects Ang-II induced apoptosis in intestinal epithelial cells. The in vitro intestinal epithelial cell apoptosis model was established by co-culturing Caco-2 cells with Ang II. Pretreatment with Angiotensin type 2 (AT2) receptor antagonist, PD123319, significantly reduced the expression of Bax and prevented the Caco-2 cells apoptosis induced by Ang II. In addition, Ang II up-regulated the expression of GATA-6. Interestingly, GATA-6 short hairpin RNA prevented Ang II-induced intestinal epithelial cells apoptosis and reduced the expression of Bax, but not Bcl-2. Taken together, the present study suggests that Angiotensin II promotes apoptosis in intestinal epithelial cells through GATA-6 and the Bax pathway in an AT2 receptor-dependent manner.« less

Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons

PubMed Central

Anand, U; Facer, P; Yiangou, Y; Sinisi, M; Fox, M; McCarthy, T; Bountra, C; Korchev, YE; Anand, P

2013-01-01

Background The angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. Methods We used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence. Results AT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas. Conclusions AT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting. PMID:23255326

Calpain-10 Activity Underlies Angiotensin II-Induced Aldosterone Production in an Adrenal Glomerulosa Cell Model

PubMed Central

Seremwe, Mutsa; Schnellmann, Rick G.

2015-01-01

Aldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases including hypertension and congestive heart failure; therefore, a complete understanding of aldosterone production is important for developing more effective treatments. Angiotensin II (AngII) regulates steroidogenesis, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence or absence of penta-EF-hands, which are involved in various cellular responses. We hypothesized that calpain, in particular calpain-10, is activated by AngII in adrenal glomerulosa cells and underlies aldosterone production. Our studies showed that pan-calpain inhibitors reduced AngII-induced aldosterone production in 2 adrenal glomerulosa cell models, primary bovine zona glomerulosa and human adrenocortical carcinoma (HAC15) cells, as well as CYP11B2 expression in the HAC15 cells. Although AngII induced calpain activation in these cells, typical calpain inhibitors had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of classical calpains in this process. However, an inhibitor of the atypical calpain, calpain-10, decreased AngII-induced aldosterone production. Consistent with this result, small interfering RNA (siRNA)-mediated knockdown of calpain-10 inhibited aldosterone production and CYP11B2 expression, whereas adenovirus-mediated overexpression of calpain-10 resulted in increased AngII-induced aldosterone production. Our results indicate that AngII-induced activation of calpain-10 in glomerulosa cells underlies aldosterone production and identify calpain-10 or its downstream pathways as potential targets for the development of drug therapies for the treatment of hypertension. PMID:25836666

Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

PubMed Central

Takahashi, Kikuyo; Matsumoto, Yasuharu; Do.e, Zhulanqiqige; Kanazawa, Masanori; Satoh, Kimio; Shimizu, Takuya; Sato, Akira; Fukumoto, Yoshihiro; Shimokawa, Hiroaki

2013-01-01

Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. Methods and Results Experimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. Conclusions Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho

Angiotensin II receptors in testes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Millan, M.A.; Aguilera, G.

Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled (Sar1,Ile8)AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration ofmore » 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.« less

Pressure-overload-induced angiotensin-mediated early remodeling in mouse heart

PubMed Central

Kim, Jeremy H.; Jiang, Ya-Ping; Cohen, Ira S.; Lin, Richard Z.; Mathias, Richard T.

2017-01-01

Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current

Angiotensin II infusion alters vascular function in mouse resistance vessels: roles of O and endothelium.

PubMed