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Sample records for modulates myocardial metabolism

  1. Modulation of cardiac metabolism during myocardial ischemia.

    PubMed

    Chagas, Antonio C P; Dourado, Paulo M M; Galvão, Tatiana de Fátima Gonçalves

    2008-01-01

    Metabolic modulation during myocardial ischemia is possible by the use of specific drugs, which may induce a shift from free fatty acid towards predominantly glucose utilization by the myocardium to increase ATP generation per unit oxygen consumption. Three agents (trimetazidine, ranolazine, and perhexiline) have well-documented anti-ischaemic effects. However, perhexiline, the most potent agent currently available, requires plasma-level monitoring to avoid hepato-neuro-toxicity. Besides, the long-term safety of trimetazidine and ranolazine has yet to be established. In addition to their effect in ischemia, the potential use of these drugs in chronic heart failure is gaining recognition as clinical and experimental data are showing the improvement of myocardial function following treatment with several of them, even in the absence of ischemia. Future applications for this line of treatment is promising and deserves additional research. In particular, large, randomised, controlled trials investigating the effects of these agents on mortality and hospitalization rates due to coronary artery disease are needed. PMID:18991673

  2. Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα

    PubMed Central

    Yang, Jing

    2016-01-01

    Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptor α (PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARα after myocardial infarction, exerting a protective effect on cardiac function. PMID:27413362

  3. Diurnal variations in myocardial metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The heart is challenged by a plethora of extracellular stimuli over the course of a normal day, each of which distinctly influences myocardial contractile function. It is therefore not surprising that myocardial metabolism also oscillates in a time-of-day dependent manner. What is becoming increasin...

  4. Cardioselective Dominant-negative Thyroid Hormone Receptor (Δ337T) Modulates Myocardial Metabolism and Contractile Dfficiency

    SciTech Connect

    Hyyti, Outi M.; Olson, Aaron; Ge, Ming; Ning, Xue-Han; Buroker, Norman E.; Chung, Youngran; Jue, Thomas; Portman, Michael A.

    2008-06-03

    Dominant- negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRβ1 mutation Δ337T. Isolated working Δ337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Δ337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV˙ O2). Unlabeled substrate Fc from endogenous sources was higher in Δ337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Δ337T. CE and Fc differences were reversed by pacing Δ337T to Con rates, accompanied by an increase in FFA Fc. Δ337T hearts lacked the ability to increase MV˙ O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Δ337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.

  5. Imaging and Modeling of Myocardial Metabolism

    PubMed Central

    Jamshidi, Neema; Karimi, Afshin; Birgersdotter-Green, Ulrika; Hoh, Carl

    2010-01-01

    Current imaging methods have focused on evaluation of myocardial anatomy and function. However, since myocardial metabolism and function are interrelated, metabolic myocardial imaging techniques, such as positron emission tomography, single photon emission tomography, and magnetic resonance spectroscopy present novel opportunities for probing myocardial pathology and developing new therapeutic approaches. Potential clinical applications of metabolic imaging include hypertensive and ischemic heart disease, heart failure, cardiac transplantation, as well as cardiomyopathies. Furthermore, response to therapeutic intervention can be monitored using metabolic imaging. Analysis of metabolic data in the past has been limited, focusing primarily on isolated metabolites. Models of myocardial metabolism, however, such as the oxygen transport and cellular energetics model and constraint-based metabolic network modeling, offer opportunities for evaluation interactions between greater numbers of metabolites in the heart. In this review, the roles of metabolic myocardial imaging and analysis of metabolic data using modeling methods for expanding our understanding of cardiac pathology are discussed. PMID:20559785

  6. [Ischemic myocardial metabolism and antianginal drugs].

    PubMed

    Ichihara, K

    1986-12-01

    The effect of several kinds of antianginal drugs: nitrates, coronary vasodilators, beta-adrenergic blocking agents and calcium entry blocking agents on the myocardial metabolism and myocardial acidosis during ischemia was studied in the dog heart in vivo. Ischemia was induced by ligating the left anterior descending coronary artery. Ischemia accelerated anaerobic metabolism in the myocardium, in which glycogen breakdown, accumulation of glycolytic intermediates, loss of high energy phosphate and tissue acidosis occurred. Nitroglycerin, beta-adrenergic blocking agents such as propranolol, and some calcium entry blocking agents such as diltiazem and flunarizine prevented the myocardial metabolism from shifting to an anaerobic metabolism in spite of ischemia. However, coronary vasodilators and the dihydropyridine type of calcium entry blocking agents were not capable of reducing changes in the myocardial metabolism and myocardial acidosis during ischemia. The author makes a point in the present review that all the drugs which dilate coronary artery are not always effective on the ischemic myocardium. PMID:3549484

  7. [Energy metabolism and myocardial function in myocardiodystrophy].

    PubMed

    Temirova, K V; Kurlygina, L A; Zavodskaia, I S; Novikova, N A

    1976-09-01

    A total of 92 patients with chronic tonsilitis and cardiovascular changes were subjected to clinical observations, ECG analysis, potassium and nitroglycerine tests, and studies of the lactic acid level and creatinekinase activity as indces of myocardial metabolism. The examinations were conducted prior to and following tonsillectomy. In a majority of patients a correlation was revealed between the degree of ECG changes and the serum lactic acid level, as well as between the ECG improvement and a reduction of the lactic acid level following tonsillectomy. Three stages of tonsillogenic myocardiodystrophy were distinguished. The obtained data indicate the rationale of the used tests for the evaluation of the myocardial meabolism alterations and of the efficacy of treatment of chronic tonsillitis patients. PMID:1011536

  8. Role of cardiomyocyte circadian clock in myocardial metabolic adaptation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marked circadian rhythmicities in cardiovascular physiology and pathophysiology exist. The cardiomyocyte circadian clock has recently been linked to circadian rhythms in myocardial gene expression, metabolism, and contractile function. For instance, the cardiomyocyte circadian clock is essential f...

  9. Quantitation of myocardial fatty acid metabolism using PET

    SciTech Connect

    Bergmann, S.R.; Weinheimer, C.J.; Markham, J.; Herrero, P.

    1996-10-01

    Abnormalities of fatty acid metabolism in the heart presage contractile dysfunction and arrhythmias. This study was performed to determine whether myocardial fatty acid metabolism could be quantified noninvasively using PET and 1-{sup 11}C-palmitate. Anesthetized dogs were studied during control conditions; during administration of dobutamine; after oxfenicine; and during infusion of glucose. Dynamic PET data after administration of 1-{sup 11}C-palmitate were fitted to a four-compartment mathematical model. Modeled rates of palmitate utilization correlated closely with directly measured myocardial palmitate and total long-chain fatty acid utilization (r = 0.93 and 0.96, respectively, p < 0.001 for each) over a wide range of arterial fatty acid levels and altered patterns of myocardial substrate use (fatty acid extraction fraction ranging from 1% to 56%, glucose extraction fraction from 1% to 16% and myocardial fatty acid utilization from 1 to 484 nmole/g/min). The percent of fatty acid undergoing oxidation could also be measured. The results demonstrate the ability to quantify myocardial fatty acid utilization with PET. The approach is readily applicable for the determination of fatty acid metabolism noninvasively in patients. 37 refs., 5 figs., 4 tabs.

  10. Circadian rhythms in myocardial metabolism and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circadian rhythms in myocardial function and dysfunction are firmly established in both animal models and humans. For example, the incidence of arrhythmias and sudden cardiac death increases when organisms awaken. Such observations have classically been explained by circadian rhythms in neurohumoral...

  11. Tomoscintigraphic assessment of myocardial metabolic heterogenity

    SciTech Connect

    Roesler, H.; Hess, T.; Weiss, M.; Noelpp, U.; Mueller, G.; Hoeflin, F.; Kinser, J.

    1983-04-01

    I-123-omega-heptadecanoic acid (HDA) was evaluated for myocardial scanning in 59 healthy volunteers and 133 patients, using a 7-pinhole collimator. Early (uptake) and late (retention) images were compared visually. Regional HDA elimination was also followed semiquantitatively based on the calculation of a retention-over-uptake ratio, R(phi), derived from the maximal counts/pixel in 60 midventricular slice sectors. The healthy heart concentrated HDA homogeneously in all segments with no difference between early and late images. The minimal R(phi), taken as representative of that myocardium with the best function, was unchanged after maximal ergometer stress and with dipyramidole-induced hyperperfusion. A circumscribed decreased HDA uptake is the clear-cut criterion for an abnormal finding. HDA tomography of the myocardium had an 86% sensitivity for myocardial infarcts (MIs) up to 4 wk old, and 83% for myocardial scars (MSs). Comparing early and late tomograms, we find a cool-warm sequence more often with acute and subacute MIs. A cool-cool or a cold-cold sequence dominated with MSs. HDA tomoscintigraphy cannot replace TI-201 for the evaluation of regional coronary reserve in coronary heart disease.

  12. Altered phosphate metabolism in myocardial infarction: P-31 MR spectroscopy

    SciTech Connect

    Bottomley, P.A.; Herfkens, R.J.; Smith, L.S.; Bashore, T.M.

    1987-12-01

    The high-energy myocardial phosphate metabolism of four patients with acute anterior myocardial infarction after coronary angioplasty and drug therapy was evaluated with cardiac-gated phosphorus magnetic resonance (MR) depth-resolved surface coil spectroscopy (DRESS) 5-9 days after the onset of symptoms. Significant reductions (about threefold) in the phosphocreatine (PCr) to inorganic phosphate (Pi) ratio and elevations in the Pi to adenosine triphosphate (ATP) ratio were observed in endocardially or transmurally derived MR spectra when compared with values from epicardially displaced spectra and values from seven healthy volunteers (P less than .05). High-energy phosphate metabolites and Pi ratios did not vary significantly during the cardiac cycle in healthy volunteers. However, contamination of Pi resonances by phosphomonoester components, including blood 2,3-diphosphoglycerate, precluded accurate spectral quantification of Pi and pH. The results indicate that localized P-31 MR spectroscopy may be used to directly assess cellular energy reserve in clinical myocardial infarction and to evaluate metabolic response to interventions.

  13. Protective metabolic effects of propranolol during total myocardial ischemia.

    PubMed

    Veronee, C D; Lewis, W R; Takla, M W; Hull-Ryde, E A; Lowe, J E

    1986-09-01

    Clinical trials have shown an increase in survival in patients treated with beta blockers after infarction. In addition, the majority of patients undergoing myocardial revascularization are also treated preoperatively with beta blockers. It is commonly thought that beta blockers exert their protective effect primarily by decreasing heart rate and subsequent myocardial work. The present study was designed to determine whether beta blockade has any primary protective metabolic effects on globally ischemic myocardium. Thirty-four anesthetized dogs underwent total myocardial ischemia at 37 degrees C. High-energy nucleotide and lactate levels in left ventricular tissue samples were determined at control and at 15 minute intervals as well as at the onset of ischemic contracture in 24 dogs. Seventeen dogs were treated with propranolol before ischemia. The time to ischemic contracture in control dogs was 63.3 +/- 1.4 minutes compared with 75.9 +/- 2.2 minutes in the propranolol-treated group (p less than 0.01). In addition to significantly delaying the onset of ischemic contracture, propranolol also decreased the rate of anaerobic glycolysis during ischemia. Ischemic contracture occurred in the control group with an average adenosine triphosphate level of 1.26 +/- 0.08 mumol compared to 0.91 +/- 0.08 mumol/gm wet weight for the beta blocked group (p less than 0.0025). These are the first data suggesting that the protective effects of beta blockade may be related to a beneficial effect on ischemic myocardial metabolism allowing myocardium to survive with lower levels of adenosine triphosphate. PMID:3018382

  14. Regional myocardial metabolism in patients with acute myocardial infarction assessed by positron emission tomography

    SciTech Connect

    Schwaiger, M.; Brunken, R.; Grover-McKay, M.; Krivokapich, J.; Child, J.; Tillisch, J.H.; Phelps, M.E.; Schelbert, H.R.

    1986-10-01

    Positron emission tomography has been shown to distinguish between reversible and irreversible ischemic tissue injury. Using this technique, 13 patients with acute myocardial infarction were studied within 72 hours of onset of symptoms to evaluate regional blood flow and glucose metabolism with nitrogen (N)-13 ammonia and fluorine (F)-18 deoxyglucose, respectively. Serial noninvasive assessment of wall motion was performed to determine the prognostic value of metabolic indexes for functional tissue recovery. Segmental blood flow and glucose utilization were evaluated using a circumferential profile technique and compared with previously established semiquantitative criteria. Relative N-13 ammonia uptake was depressed in 32 left ventricular segments. Sixteen segments demonstrated a concordant decrease in flow and glucose metabolism. Regional function did not change over time in these segments. In contrast, 16 other segments with reduced blood flow revealed maintained F-18 deoxyglucose uptake consistent with remaining viable tissue. The average wall motion score improved significantly in these segments (p less than 0.01), yet the degree of recovery varied considerably among patients. Coronary anatomy was defined in 9 of 13 patients: patent infarct vessels supplied 8 of 10 segments with F-18 deoxyglucose uptake, while 10 of 13 segments in the territory of an occluded vessel showed concordant decreases in flow and metabolism (p less than 0.01). Thus, positron emission tomography reveals a high incidence of residual tissue viability in ventricular segments with reduced flow and impaired function during the subacute phase of myocardial infarction. Absence of residual tissue metabolism is associated with irreversible injury, while preservation of metabolic activity identifies segments with a variable outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment*

    PubMed Central

    Wentz, Anna E.; d'Avignon, D. André; Weber, Mary L.; Cotter, David G.; Doherty, Jason M.; Kerns, Robnet; Nagarajan, Rakesh; Reddy, Naveen; Sambandam, Nandakumar; Crawford, Peter A.

    2010-01-01

    Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferator-activated receptor α-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial 13C enrichment of glutamate when 13C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states. PMID:20529848

  16. Myocardial Reloading After Extracorporeal Membrane Oxygenation Alters Substrate Metabolism While Promoting Protein Synthesis

    PubMed Central

    Kajimoto, Masaki; O'Kelly Priddy, Colleen M.; Ledee, Dolena R.; Xu, Chun; Isern, Nancy; Olson, Aaron K.; Rosiers, Christine Des; Portman, Michael A.

    2013-01-01

    Background Extracorporeal membrane oxygenation (ECMO) unloads the heart, providing a bridge to recovery in children after myocardial stunning. ECMO also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with ECMO modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. Methods and Results Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8‐hour ECMO (UNLOAD) and postwean from ECMO (RELOAD). We infused into the coronary artery [2‐13C]‐pyruvate as an oxidative substrate and [13C6]‐L‐leucine as an indicator for amino acid oxidation and protein synthesis. Upon RELOAD, each functional parameter, which were decreased substantially by ECMO, recovered to near‐baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to UNLOAD, RELOAD altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl‐CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all CAC intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%). Conclusions RELOAD alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the CAC. Improved understanding of factors governing these metabolic perturbations may

  17. Myocardial Reloading after Extracorporeal Membrane Oxygenation Alters Substrate Metabolism While Promoting Protein Synthesis

    SciTech Connect

    Kajimoto, Masaki; Priddy, Colleen M.; Ledee, Dolena; Xu, Chun; Isern, Nancy G.; Olson, Aaron; Des Rosiers, Christine; Portman, Michael A.

    2013-08-19

    Extracorporeal membrane oxygenation (ECMO) unloads the heart providing a bridge to recovery in children after myocardial stunning. Mortality after ECMO remains high.Cardiac substrate and amino acid requirements upon weaning are unknown and may impact recovery. We assessed the hypothesis that ventricular reloading modulates both substrate entry into the citric acid cycle (CAC) and myocardial protein synthesis. Fourteen immature piglets (7.8-15.6 kg) were separated into 2 groups based on ventricular loading status: 8 hour-ECMO (UNLOAD) and post-wean from ECMO (RELOAD). We infused [2-13C]-pyruvate as an oxidative substrate and [13C6]-L-leucine, as a tracer of amino acid oxidation and protein synthesis into the coronary artery. RELOAD showed marked elevations in myocardial oxygen consumption above baseline and UNLOAD. Pyruvate uptake was markedly increased though RELOAD decreased pyruvate contribution to oxidative CAC metabolism.RELOAD also increased absolute concentrations of all CAC intermediates, while maintaining or increasing 13C-molar percent enrichment. RELOAD also significantly increased cardiac fractional protein synthesis rates by >70% over UNLOAD. Conclusions: RELOAD produced high energy metabolic requirement and rebound protein synthesis. Relative pyruvate decarboxylation decreased with RELOAD while promoting anaplerotic pyruvate carboxylation and amino acid incorporation into protein rather than to the CAC for oxidation. These perturbations may serve as therapeutic targets to improve contractile function after ECMO.

  18. Noninvasive measurement of regional myocardial glucose metabolism by positron emission computed tomography. [Dogs

    SciTech Connect

    Schelbert, H.R.; Phelps, M.E.

    1980-06-01

    While the results of regional myocardial glucose metabolism measurements using positron emission computed tomography (/sup 13/N-ammonia) are promising, their utility and value remains to be determined in man. If this technique can be applied to patients with acute myocardial ischemia or infarction it may permit delineation of regional myocardial segments with altered, yet still active metabolism. Further, it may become possible to evaluate the effects of interventions designed to salvage reversibly injured myocardium by this technique.

  19. Polyamine metabolism in rat myocardial ischemia-reperfusion injury.

    PubMed

    Han, Liping; Xu, Changqing; Guo, Yimin; Li, Hongzhu; Jiang, Chunming; Zhao, Yajun

    2009-02-01

    This study was focused on investigating the involvement of polyamine metabolism in the myocardial ischemia-reperfusion injury (MIRI) in an in vivo rat model. A branch of the descending left coronary artery was occluded for 30 min followed by 2 h, 6 h, 12 h, and 24 h reperfusion. Then the expression of spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) and the concentrations of polyamines were assessed. It was found that the expression of SSAT and ODC were upregulated after reperfusion and the concentrations of spermidine and spermine were significantly decreased, while putrescine concentration was significantly increased. The results suggest that MIRI may cause disturbance of polyamine metabolism, and it may play a critical role in MIRI. PMID:18077014

  20. The effect of nifedipine on myocardial perfusion and metabolism in systemic sclerosis. A positron emission tomographic study

    SciTech Connect

    Duboc, D.; Kahan, A.; Maziere, B.; Loc'h, C.; Crouzel, C.; Menkes, C.J.; Amor, B.; Strauch, G.; Guerin, F.; Syrota, A. )

    1991-02-01

    We assessed the effect of nifedipine on myocardial perfusion and metabolism in 9 patients with systemic sclerosis, using positron emission tomography with a perfusion tracer (potassium-38) and a metabolic tracer (18F-fluorodeoxyglucose (18FDG)). Nifedipine, 20 mg 3 times daily for 1 week, induced a significant increase in 38K myocardial uptake, a significant decrease in 18FDG myocardial uptake, and a significant increase in the myocardial 38K: 18FDG ratio. These results indicate that the increase in myocardial perfusion is associated with modifications in myocardial energy metabolism, which probably result from a beneficial anti-ischemic effect of nifedipine in patients with systemic sclerosis.

  1. Succinate metabolism: a new therapeutic target for myocardial reperfusion injury.

    PubMed

    Pell, Victoria R; Chouchani, Edward T; Frezza, Christian; Murphy, Michael P; Krieg, Thomas

    2016-07-15

    Myocardial ischaemia/reperfusion (IR) injury is a major cause of death worldwide and remains a disease for which current clinical therapies are strikingly deficient. While the production of mitochondrial reactive oxygen species (ROS) is a critical driver of tissue damage upon reperfusion, the precise mechanisms underlying ROS production have remained elusive. More recently, it has been demonstrated that a specific metabolic mechanism occurs during ischaemia that underlies elevated ROS at reperfusion, suggesting a unifying model as to why so many different compounds have been found to be cardioprotective against IR injury. This review will discuss the role of the citric acid cycle intermediate succinate in IR pathology focusing on the mechanism by which this metabolite accumulates during ischaemia and how it can drive ROS production at Complex I via reverse electron transport. We will then examine the potential for manipulating succinate accumulation and metabolism during IR injury in order to protect the heart against IR damage and discuss targets for novel therapeutics designed to reduce reperfusion injury in patients. PMID:27194563

  2. Metabolic modulation and cellular therapy of cardiac dysfunction and failure

    PubMed Central

    Revenco, Diana; Morgan, James P

    2009-01-01

    Abstract At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy. PMID:19382894

  3. Myocardial Function and Lipid Metabolism in the Chronic Alcoholic Animal

    PubMed Central

    Regan, Timothy J.; Khan, Mohammad I.; Ettinger, Philip O.; Haider, Bunyad; Lyons, Michael M.; Oldewurtel, Henry A.; Weber, Marilyn

    1974-01-01

    In view of the variables that obscure the pathogenesis of cardiomyopathy, a study was undertaken in mongrel dogs fed ethanol as 36% of calories for up to 22 mo. Both the experimental and control groups maintained body weight, hematocrit, plasma vitamin, and protein levels. Left ventricular function was evaluated in the intact anesthetized dog using indicator dilution for end-diastolic and stroke volume determinations. During increased afterload with angiotensin, the ethanol group exhibited a larger rise of end-diastolic pressure (P<0.01), whereas end-diastolic and stroke volume responses were significantly less than in controls. Preload increments with saline elicited a significantly higher end-diastolic pressure rise in the ethanol group (P<0.01). No hypertrophy, inflammation, or fibrosis was present and it was postulated that the enhanced diastolic stiffness was related to accumulation of Alcian Blue-positive material in the ventricular interstitium. To evaluate myocardial lipid metabolism, [1-14C]oleic acid was infused systemically. Plasma specific activity and myocardial lipid uptake were similar in both groups. There was a significantly increased incorporation of label into triglyceride, associated with a reduced 14CO2 production, considered the basis for a twofold increment of triglyceride content. In addition, diminished incorporation of [14C]oleic acid into phospholipid was observed accompanied by morphologic abnormalities of cardiac cell membranes. Potassium loss and sodium gain, like the lipid alteration, was more prominent in the subendocardium. Thus, chronic ethanol ingestion in this animal model is associated with abnormalities of ventricular function without evident malnutrition, analogous to the preclinical malfunction described in the human alcoholic. Images PMID:4368946

  4. Myocardial imaging and metabolic studies with (17-/sup 123/I)iodoheptadecanoic acid

    SciTech Connect

    Freundlieb, C.; Hoeck, A.; Vyska, K.; Feinendegen, L.E.; Machulla, H.J.; Stoecklin, G.

    1980-11-01

    After intravenous administration of the stearic acid analogue (17-/sup 123/I)iodoheptadecanoic acid (I-123 HA), myocardial metabolism was studied in ten normal individuals, eight patients with coronary artery disease and three patients with congestive heart failure. High-quality images were obtained in sequential scintigraphy of I-123 metabolically bound in myocardial tissue. Infarcted zones as well as ischemic regions are indicated by reduced tracer uptake. Iodine-123 in the blood pool and interstitial space consists mainly of radioiodide that is liberated by fatty-acid metabolism and was corrected for. Using the proposed correction not only are the images improved but the uptake and elimination of the I-123 in the myocardial cells can be followed. The average disappearance half-time of I-123 HA from the myocardium of normal persons was 24 +- 4.7 min. In patients with coronary artery disease significant differences between myocardial regions were observed.

  5. Myocardial Energy Substrate Metabolism in Heart Failure : from Pathways to Therapeutic Targets.

    PubMed

    Fukushima, Arata; Milner, Kenneth; Gupta, Abhishek; Lopaschuk, Gary D

    2015-01-01

    Despite recent advances in therapy, heart failure remains a major cause of mortality and morbidity and is a growing healthcare burden worldwide. Alterations in myocardial energy substrate metabolism are a hallmark of heart failure, and are associated with an energy deficit in the failing heart. Previous studies have shown that a metabolic shift from mitochondrial oxidative metabolism to glycolysis, as well as an uncoupling between glycolysis and glucose oxidation, plays a crucial role in the development of cardiac inefficiency and functional impairment in heart failure. Therefore, optimizing energy substrate utilization, particularly by increasing mitochondrial glucose oxidation, can be a potentially promising approach to decrease the severity of heart failure by improving mechanical cardiac efficiency. One approach to stimulating myocardial glucose oxidation is to inhibit fatty acid oxidation. This review will overview the physiological regulation of both myocardial fatty acid and glucose oxidation in the heart, and will discuss what alterations in myocardial energy substrate metabolism occur in the failing heart. Furthermore, lysine acetylation has been recently identified as a novel post-translational pathway by which mitochondrial enzymes involved in all aspects of cardiac energy metabolism can be regulated. Thus, we will also discuss the effect of acetylation of metabolic enzymes on myocardial energy substrate preference in the settings of heart failure. Finally, we will focus on pharmacological interventions that target enzymes involved in fatty acid uptake, fatty acid oxidation, transcriptional regulation of fatty acid oxidation, and glucose oxidation to treat heart failure. PMID:26166604

  6. Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction.

    PubMed

    Barry, James S; Rozance, Paul J; Brown, Laura D; Anthony, Russell V; Thornburg, Kent L; Hay, William W

    2016-04-01

    Unlike other visceral organs, myocardial weight is maintained in relation to fetal body weight in intrauterine growth restriction (IUGR) fetal sheep despite hypoinsulinemia and global nutrient restriction. We designed experiments in fetal sheep with placental insufficiency and restricted growth to determine basal and insulin-stimulated myocardial glucose and oxygen metabolism and test the hypothesis that myocardial insulin sensitivity would be increased in the IUGR heart. IUGR was induced by maternal hyperthermia during gestation. Control (C) and IUGR fetal myocardial metabolism were measured at baseline and under acute hyperinsulinemic/euglycemic clamp conditions at 128-132 days gestation using fluorescent microspheres to determine myocardial blood flow. Fetal body and heart weights were reduced by 33% (P = 0.008) and 30% (P = 0.027), respectively. Heart weight to body weight ratios were not different. Basal left ventricular (LV) myocardial blood flow per gram of LV tissue was maintained in IUGR fetuses compared to controls. Insulin increased LV myocardial blood flow by ∼38% (P < 0.01), but insulin-stimulated LV myocardial blood flow in IUGR fetuses was 73% greater than controls. Similar to previous reports testing acute hypoxia, LV blood flow was inversely related to arterial oxygen concentration (r(2 )= 0.71) in both control and IUGR animals. Basal LV myocardial glucose delivery and uptake rates were not different between IUGR and control fetuses. Insulin increased LV myocardial glucose delivery (by 40%) and uptake (by 78%) (P < 0.01), but to a greater extent in the IUGR fetuses compared to controls. During basal and hyperinsulinemic-euglycemic clamp conditions LV myocardial oxygen delivery, oxygen uptake, and oxygen extraction efficiency were not different between groups. These novel results demonstrate that the fetal heart exposed to nutrient and oxygen deprivation from placental insufficiency appears to maintain myocardial energy supply

  7. On functional module detection in metabolic networks.

    PubMed

    Koch, Ina; Ackermann, Jörg

    2013-01-01

    Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady-state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models. PMID:24958145

  8. On Functional Module Detection in Metabolic Networks

    PubMed Central

    Koch, Ina; Ackermann, Jörg

    2013-01-01

    Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady-state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models. PMID:24958145

  9. Metabolic therapy at the crossroad: how to optimize myocardial substrate utilization?

    PubMed

    Kolwicz, Stephen C; Tian, Rong

    2009-08-01

    There has been growing interest in targeting myocardial substrate metabolism for the therapy of cardiovascular and metabolic diseases. This is largely based on the observation that cardiac metabolism undergoes significant changes during both physiologic and pathologic stresses. In search for an effective therapeutic strategy, recent studies have focused on the functional significance of the substrate switch in the heart during stress conditions, such as cardiac hypertrophy and failure, using both pharmacologic and genetic approaches. The results of these studies indicate that both the capacity and the flexibility of the cardiac metabolic network are essential for normal function; thus, their maintenance should be the primary goal for future metabolic therapy. PMID:20211436

  10. Metabolic Therapy at the Crossroad: How to optimize myocardial substrate utilization?

    PubMed Central

    Kolwicz, Stephen C.; Tian, Rong

    2010-01-01

    There has been growing interest in targeting myocardial substrate metabolism for the therapy of cardiovascular and metabolism diseases. This is largely based on the observation that cardiac metabolism undergoes significant changes during both physiological and pathological stresses. In search for an effective therapeutic strategy, recent studies have focused on the functional significance of the substrate switch in the heart during stress conditions, such as cardiac hypertrophy and failure, using both pharmacological and genetic approaches. The results of these studies indicate that both the capacity and the flexibility of the cardiac metabolic network are essential for normal function; thus, their maintenance should be the primary goal for future metabolic therapy. PMID:20211436

  11. Myocardial depression by ketamine. Haemodynamic and metabolic observations in animals.

    PubMed

    Chamberlain, J H; Seed, R G; Undre, N

    1981-04-01

    This study investigated the effect of ketamine on myocardial function. In dogs the drug was infused directly into the left main coronary artery. The concentration chosen was similar to the peak concentration found following a bolus intravenous injection. A mild depression of inotropic state was found which recovered completely after stopping the infusion. Myocardial depression was confirmed in a guinea pig Langendorff preparation. No changes in high energy phosphates were found in these hearts after 45-60 minutes of perfusion with ketamine in the perfusion medium. This study confirms that myocardial depression occurs with ketamine but suggests that it is unlikely to be of clinical significance. Depletion of high energy phosphates did not seem to be the cause of the depression. PMID:7246986

  12. [Effects of dichloroacetate in the ischemic heart. Analysis of hemodynamics, myocardial energy metabolism and myocardial pH].

    PubMed

    Mizushima, M

    1990-05-01

    The effects of dichloroacetate (DCA), which is known to have a beneficial effect on lactic acidosis, were examined on myocardial acidosis during coronary occlusion in dogs. Ischemia was induced by complete ligation of the left anterior descending coronary artery (LAD) of the open-chest dog heart. DCA 100 mg/kg or 200 mg/kg was administered intravenously 10 or 60 min prior to the occlusion of LAD. DCA did not change the LAD flow, decreased heart rate, increased both systolic and diastolic blood pressures transiently. LAD occlusion significantly increased the ST segment of the epicardial ECG in the saline-treated group. DCA administered prior to the LAD occlusion caused 50% decrease of the elevation in ST segment during ischemia. Ischemia accelerated anaerobic metabolism in the myocardium; the levels of glycogen, adenosine triphosphate (ATP) and creatine phosphate (CP) decreased, and lactate increased during ischemia. Calculated energy charge potential was decreased, and [( G6P] + [F6P])/[FDP] ratio was increased by ischemia. The decreased levels of glycogen, ATP, CP in DCA-treated group were similar to those in saline-treated group during 3 min ischemia. Pretreatment of DCA reduced the accumulation of myocardial lactate by ischemia. There were no differences in variables except myocardial lactate levels between DCA 100 mg/kg and 200 mg/kg. The myocardial lactate levels were lower in both nonischemic and ischemic dogs by DCA 200 mg/kg than DCA 100 mg/kg. DCA did not change either the ATP levels or energy charge potential during both ischemia and reperfusion. LAD occlusion caused a significant decrease of myocardial pH from 7.51 to 6.83 in saline-treated group, while it produced only a small decrease in DCA-treated group from 7.56 to 7.35.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2379912

  13. Positron emission tomography detects tissue metabolic activity in myocardial segments with persistent thallium perfusion defects

    SciTech Connect

    Brunken, R.; Schwaiger, M.; Grover-McKay, M.; Phelps, M.E.; Tillisch, J.; Schelbert, H.R.

    1987-09-01

    Positron emission tomography with /sup 13/N-ammonia and /sup 18/F-2-deoxyglucose was used to assess myocardial perfusion and glucose utilization in 51 myocardial segments with a stress thallium defect in 12 patients. Myocardial infarction was defined by a concordant reduction in segmental perfusion and glucose utilization, and myocardial ischemia was identified by preservation of glucose utilization in segments with rest hypoperfusion. Of the 51 segments studied, 36 had a fixed thallium defect, 11 had a partially reversible defect and 4 had a completely reversible defect. Only 15 (42%) of the 36 segments with a fixed defect and 4 (36%) of the 11 segments with a partially reversible defect exhibited myocardial infarction on study with positron tomography. In contrast, residual myocardial glucose utilization was identified in the majority of segments with a fixed (58%) or a partially reversible (64%) thallium defect. All of the segments with a completely reversible defect appeared normal on positron tomography. Apparent improvement in the thallium defect on delayed images did not distinguish segments with ischemia from infarction. Thus, positron emission tomography reveals evidence of persistent tissue metabolism in the majority of segments with a fixed or partially resolving stress thallium defect, implying that markers of perfusion alone may underestimate the extent of viable tissue in hypoperfused myocardial segments.

  14. Oligophrenin1 protects mice against myocardial ischemia and reperfusion injury by modulating inflammation and myocardial apoptosis.

    PubMed

    Niermann, Christina; Gorressen, Simone; Klier, Meike; Gowert, Nina S; Billuart, Pierre; Kelm, Malte; Merx, Marc W; Elvers, Margitta

    2016-08-01

    The Rho family of small GTPases has been analyzed in cardiac physiology and pathophysiology including myocardial infarction (MI) in the last years. Contradictory results show either a protective or a declined effect of RhoA and the RhoA effector Rho-associated protein kinase (ROCK) in myocardial ischemia and reperfusion injury that is associated with cardiomyocyte survival and caspase-3 activation. Cardiac-specific deletion of Rac1 reduced ischemia reperfusion injury in diabetic hearts, whereas cardiomyocyte specific overexpression of active Rac1 predisposes the heart to increased myocardial injury with enhanced contractile dysfunction. GTPase-activating proteins (GAPs) control the activation of Rho proteins through stimulation of GTP hydrolysis. However, the impact of GAPs in myocardial ischemia and reperfusion injury remains elusive. Here we analyzed the role of oligophrenin1 (OPHN1), a RhoGAP with Bin/Amphiphysin/Rvs (BAR) domain known to regulate the activity of RhoA, Rac1 and Cdc42 in MI. The expression of Ophn1, RhoA and Rac1 is strongly upregulated 24h after myocardial ischemia. Loss of OPHN1 induced enhanced activity of Rho effector molecules leading to elevated cardiomyocyte apoptosis and increased migration of inflammatory cells into the infarct border zone of OPHN1 deficient mice. Consequently, echocardiography 24h after myocardial ischemia revealed declined left ventricle function in OPHN1 deficient mice. Our results indicate that OPHN1 mediated regulation of RhoA, Rac1 and Cdc42 is crucial for the preservation of cardiac function after myocardial injury. PMID:27117132

  15. Circadian rhythms in myocardial metabolism and contractile function; influence of workload and oleate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multiple extra-cardiac stimuli, such as workload and circulating nutrients (e.g., fatty acids), known to influence myocardial metabolism and contractile function exhibit marked circadian rhythms. The aim of the present study was to investigate whether the rat heart exhibits circadian rhythms in its ...

  16. A “PET” area of interest: myocardial metabolism in human systolic heart failure

    PubMed Central

    Kadkhodayan, Ana; Coggan, Andrew R.; Peterson, Linda R.

    2013-01-01

    Myocardial substrate metabolism provides the energy needed for cardiac contraction and relaxation. The normal adult heart uses predominantly fatty acids (FAs) as its primary fuel source. However, the heart can switch and use glucose (and to a lesser extent, ketones, lactate, as well as endogenous triglycerides and glycogen), depending on the metabolic milieu and superimposed conditions. FAs are not a wholly better fuel than glucose, but they do provide more energy per mole than glucose. Conversely, glucose is the more oxygen-efficient fuel. Studies in animal models of heart failure (HF) fairly consistently demonstrate a shift away from myocardial fatty acid metabolism and towards glucose metabolism. Studies in humans are less consistent. Some show the same metabolic switch away from FA metabolism but not all. This may be due to differences in the etiology of HF, sex-related differences, or other mitigating factors. For example, obesity, insulin resistance, and diabetes are all related to an increased risk of HF and may complicate or contribute to its development. However, these conditions are associated with increased FA metabolism. This review will discuss aspects of human heart metabolism in systolic dysfunction as measured by the noninvasive, quantitative method – positron emission tomography. Continued research in this area is vital if we are to ameliorate HF by manipulating heart metabolism with the aim of increasing energy production and/or efficiency. PMID:23180281

  17. Different effects of interventions suppressing free fatty acid metabolism on myocardial ischemia.

    PubMed

    Kahles, H; Hellige, G; Hunnemann, D H; Junggeburth, J; Kochsiek, K

    1984-06-01

    We studied the effects of different metabolic interventions, which stimulate oxidative myocardial carbohydrate metabolism, on ischemic stress during repeated coronary occlusions of three minutes in open-chest dog hearts. Increase of glucose concentration in plasma and decrease of peripheral lipolysis by glucose-insulin-potassium (n = 6) had no substantial beneficial effects on myocardial damage indicated by hemodynamic, electrocardiographic, and metabolic parameters. Infusion of lactate and pyruvate (10 mM, n = 6) was detrimental. Only activation of pyruvate dehydrogenase by dichloroacetate (n = 6) without influence on plasma osmolality reduced epicardial ST-segment elevations (-42%) and myocardial release of potassium (-36%), phosphate (-58%), and lactate (-39%). Elevations of plasma osmolalities by 10 and 20 mOsm with the metabolically inert mannitol increased ECG changes, functional loss and release of potassium, phosphate, and lactate during ischemia in our model. It is suggested, that the oxygen-saving potency of metabolic interventions can exert univocal beneficial effects in experimental and in clinical conditions only when systemic hyperosmolality and hypervolemia are avoided. PMID:6430618

  18. Pilot Study of Pioglitazone and Exercise Training Effects on Basal Myocardial Substrate Metabolism and Left Ventricular Function in HIV-Positive Individuals with Metabolic Complications

    PubMed Central

    Cade, W. Todd; Reeds, Dominic N.; Overton, E. Turner; Herrero, Pilar; Waggoner, Alan D.; Laciny, Erin; Bopp, Coco; Lassa-Claxton, Sherry; Gropler, Robert J.; Peterson, Linda R.; Yarasheski, Kevin E.

    2014-01-01

    Background Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. Objective In a pilot study, we evaluated whether the peroxisome proliferator–activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. Design Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90–120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. Results Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. Conclusions PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications. PMID:24334183

  19. The role of CD36 in the regulation of myocardial lipid metabolism.

    PubMed

    Kim, Ty T; Dyck, Jason R B

    2016-10-01

    Since the heart has one of the highest energy requirements of all organs in the body, it requires a constant and plentiful supply of fuel to function properly. Mitochondrial oxidation of lipids provides a major source of ATP for the heart, and the cellular processes that regulate lipid uptake and utilization are important contributors to maintaining proper myocardial energetic status. Although numerous proteins are coordinately regulated in order to ensure proper fatty acid utilization in the cardiomyocyte, a key first step in this process is the entry of fatty acids into the cell. An important protein involved in the transport of fatty acids into the cardiomyocyte is the plasma membrane-associated protein known as fatty acid translocase (FAT; also known as CD36). While multiple proteins are involved in facilitating fatty acid uptake in the heart, CD36 accounts for approximately 50-70% of the total fatty acid taken up in cardiomyocytes. As such, myocardial metabolism of fatty acids may depend upon proper CD36 function. Consistent with this, changes in CD36 levels/function have been implicated in the alteration of myocardial metabolism in the pathophysiology of certain cardiovascular diseases. As such, a better understanding of the role and function of CD36 in the heart may provide important insights for the development of new treatments for specific cardiovascular diseases. Herein, we review the role of CD36 in myocardial lipid metabolism in the healthy heart and describe how CD36-mediated alterations in lipid metabolism may contribute to cardiovascular disease. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk. PMID:26995462

  20. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy

    PubMed Central

    Tricò, Domenico; Baldi, Simona; Frascerra, Silvia; Venturi, Elena; Marraccini, Paolo; Neglia, Danilo; Natali, Andrea

    2016-01-01

    Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p < 0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 μmol/min/gO2 equivalents, p < 0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217. PMID:26798650

  1. Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy.

    PubMed

    Tricò, Domenico; Baldi, Simona; Frascerra, Silvia; Venturi, Elena; Marraccini, Paolo; Neglia, Danilo; Natali, Andrea

    2016-01-01

    Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p < 0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 μmol/min/gO2 equivalents, p < 0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217. PMID:26798650

  2. In Vivo Metabolic Phenotyping of Myocardial Substrate Metabolism in Rodents: Differential Efficacy of Metformin and Rosiglitazone Monotherapy

    PubMed Central

    Shoghi, Kooresh I.; Finck, Brian N.; Schechtman, Kenneth B.; Sharp, Terry; Herrero, Pilar; Gropler, Robert J.; Welch, Michael J.

    2009-01-01

    Background Cardiovascular disease is the leading cause of death among diabetic patients with alterations in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of Metformin and Rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type-2 diabetes mellitus. Methods and Results The study utilized 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with Metformin (16.6mg/kg/day) and a group treated with Rosiglitazone (4mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small animal PET to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO) and esterification (MFAE). Treatment lasted for 5 weeks following baseline imaging. At week 19, rats were sacrificed and hearts extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography (ECHO) measurements were obtained at week 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, Rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4 while diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study. Conclusions Treatment with Rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart. PMID:19808625

  3. Dichloroacetate attenuates myocardial acidosis and metabolic changes induced by partial occlusion of the coronary artery in dogs.

    PubMed

    Sakai, K; Ichihara, K; Nasa, Y; Kamigaki, M; Abiko, Y

    1990-01-01

    The present study was undertaken to examine whether dichloroacetate, which inhibits pyruvate dehydrogenase kinase and, therefore, increases the activity of pyruvate dehydrogenase, attenuates myocardial acidosis and metabolic changes induced by coronary occlusion. In dogs anesthetized with pentobarbital, the left anterior descending coronary artery was incompletely occluded to reduce the left anterior descending flow to a half to one third of the original flow (partial occlusion) to produce myocardial (regional) ischemia. Partial occlusion was continued for 90 min, and a bolus injection of saline or dichloroacetate was made intravenously 30 min after the onset of occlusion. Partial occlusion decreased myocardial pH significantly. An injection of dichloroacetate (150 mg/kg) increased myocardial pH that had been lowered by partial occlusion. Myocardial metabolites were measured in other dogs. Partial occlusion decreased the myocardial levels of adenosine triphosphate, creatine phosphate and energy charge potential, and increased that of lactate significantly, without affecting the myocardial levels of pyruvate and nonesterified fatty acids. Dichloroacetate attenuated the ischemia-induced changes in the myocardial levels of adenosine triphosphate, creatine phosphate, energy charge potential and lactate. These results indicate that dichloroacetate attenuates the myocardial acidosis and metabolic changes during coronary partial occlusion. PMID:2095718

  4. Myocardial oxidative metabolism and protein synthesis during mechanical circulatory support by extracorporeal membrane oxygenation

    PubMed Central

    Priddy, Colleen M. O′Kelly; Kajimoto, Masaki; Ledee, Dolena R.; Bouchard, Bertrand; Isern, Nancy; Olson, Aaron K.; Rosiers, Christine Des

    2013-01-01

    Extracorporeal membrane oxygenation (ECMO) provides essential mechanical circulatory support necessary for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur, which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative metabolism and protein synthesis. We focused on the amino acid leucine and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart 1) the fractional contribution of leucine (FcLeucine) and pyruvate to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and 2) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 h of normal circulation or ECMO) and intracoronary infusion [13C6,15N]-L-leucine (3.7 mM) alone or with [2-13C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (∼40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining 1) metabolic flexibility indicated by ability to respond to pyruvate and 2) a normal or increased capacity for global protein synthesis. PMID:23203964

  5. Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy

    SciTech Connect

    Cannon, R.O. 3d.; Dilsizian, V.; O'Gara, P.T.; Udelson, J.E.; Schenke, W.H.; Quyyumi, A.; Fananapazir, L.; Bonow, R.O. )

    1991-05-01

    Exercise-induced abnormalities during thallium-201 scintigraphy that normalize at rest frequently occur in patients with hypertrophic cardiomyopathy. However, it is not known whether these abnormalities are indicative of myocardial ischemia. Fifty patients with hypertrophic cardiomyopathy underwent exercise {sup 201}Tl scintigraphy and, during the same week, measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Thirty-seven patients (74%) had one or more {sup 201}Tl abnormalities that completely normalized after 3 hours of rest; 26 had regional myocardial {sup 201}Tl defects, and 26 had apparent left ventricular cavity dilatation with exercise, with 15 having coexistence of these abnormal findings. Of the 37 patients with reversible {sup 201}Tl abnormalities, 27 (73%) had metabolic evidence of myocardial ischemia during rapid atrial pacing compared with four of 13 patients (31%) with normal {sup 201}Tl scans (p less than 0.01). Eleven patients had apparent cavity dilatation as their only {sup 201}Tl abnormality; their mean postpacing left ventricular end-diastolic pressure was significantly higher than that of the 13 patients with normal {sup 201}Tl studies (33 +/- 5 versus 21 +/- 10 mm Hg, p less than 0.001). There was no correlation between the angiographic presence of systolic septal or epicardial coronary arterial compression and the presence or distribution of {sup 201}Tl abnormalities. Patients with ischemic ST segment responses to exercise had an 80% prevalence rate of reversible {sup 201}Tl abnormalities and a 70% prevalence rate of pacing-induced ischemia. However, 69% of patients with nonischemic ST segment responses had reversible {sup 201}Tl abnormalities, and 55% had pacing-induced ischemia. Reversible {sup 201}Tl abnormalities during exercise stress are markers of myocardial ischemia in hypertrophic cardiomyopathy and most likely identify relatively underperfused myocardium.

  6. [Modifications in myocardial energy metabolism in diabetic patients

    NASA Technical Reports Server (NTRS)

    Grynberg, A.

    2001-01-01

    The capacity of cardiac myocyte to regulate ATP production to face any change in energy demand is a major determinant of cardiac function. Because FA is the main heart fuel (although the most expensive one in oxygen, and prompt to induce deleterious effects), this process is based on a balanced fatty acid (FA) metabolism. Several pathological situations are associated with an accumulation of FA or derivatives, or with an excessive b-oxidation. The diabetic cardiomyocyte is characterised by an over consumption of FA. The control of the FA/glucose balance clearly appears as a new strategy for cytoprotection, particularly in diabetes and requires a reduced FA contribution to ATP production. Cardiac myocytes can control FA mitochondrial entry, but display weak ability to control FA uptake, thus the fate of non beta-oxidized FA appear as a new impairment for the cell. Both the trigger and the regulation of cardiac contraction result from membrane activity, and the other major FA function in the myocardium is their role in membrane homeostasis, through the phospholipid synthesis and remodeling pathways. Sudden death, hypercatecholaminemia, diabetes and heart failure have been associated with an altered PUFA content in cardiac membranes. Experimental data suggest that the 2 metabolic pathways involved in membrane homeostasis may represent therapeutic targets for cytoprotection. The drugs that increase cardiac phospholipid turnover (trimetazidine, ranolazine,...) display anti-ischemic non hemodynamic effect. This effect is based on a redirection of FA utilization towards phospholipid synthesis, which decrease their availability for energy production. A nutritional approach gave also promising results. Besides its anti-arrhythmic effect, the dietary docosahexaenoic acid is able to reduce FA energy consumption and hence oxygen demand. The cardiac metabolic pathways involving FA should be considered as a whole, precariously balanced. The diabetic heart being characterised by

  7. Modeling to link regional myocardial work, metabolism and blood flows

    PubMed Central

    Bassingthwaighte, James B.; Beard, Daniel A; Carlson, Brian E.; Dash, Ranjan K.; Vinnakota, Kalyan

    2012-01-01

    Given the mono-functional, highly coordinated processes of cardiac excitation and contraction, the observations that regional myocardial blood flows, rMBF, are broadly heterogeneous has provoked much attention, but a clear explanation has not emerged. In isolated and in vivo heart studies the total coronary flow is found to be proportional to the rate-pressure product (systolic mean blood pressure times heart rate), a measure of external cardiac work. The same relationship might be expected on a local basis: more work requires more flow. The validity of this expectation has never been demonstrated experimentally. In this article we review the concepts linking cellular excitation and contractile work to cellular energetics and ATP demand, substrate utilization, oxygen demand, vasoregulation, and local blood flow. Mathematical models of these processes are now rather well developed. We propose that the construction of an integrated model encompassing the biophysics, biochemistry and physiology of cardiomyocyte contraction, then combined with a detailed three-dimensional structuring of the fiber bundle and sheet arrangements of the heart as a whole will frame an hypothesis that can be quantitatively evaluated to settle the prime issue: Does local work drive local flow in a predictable fashion that explains the heterogeneity? While in one sense one can feel content that work drives flow is irrefutable, there are no cardiac contractile models that demonstrate the required heterogeneity in local strain-stress-work; quite the contrary, cardiac contraction models have tended toward trying to show that work should be uniform. The object of this review is to argue that uniformity of work does not occur, and is impossible in any case, and that further experimentation and analysis are necessary to test the hypothesis. PMID:22915334

  8. Myocyte repolarization modulates myocardial function in aging dogs.

    PubMed

    Sorrentino, Andrea; Signore, Sergio; Qanud, Khaled; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A; Wunimenghe, Oriyanhan; Michler, Robert E; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G; Anversa, Piero; Hintze, Thomas H; Rota, Marcello

    2016-04-01

    Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. PMID:26801307

  9. Size of myocardial infarction induced by ischaemia/reperfusion is unaltered in rats with metabolic syndrome.

    PubMed

    Thim, Troels; Bentzon, Jacob F; Kristiansen, Steen B; Simonsen, Ulf; Andersen, Heidi L; Wassermann, Karsten; Falk, Erling

    2006-06-01

    Obesity is associated with metabolic syndrome and increased incidence of and mortality from myocardial infarction. The aim of the present study was to develop an animal model with metabolic syndrome and examine how that influences size of myocardial infarcts induced by occlusion and reperfusion of the left anterior descending coronary artery. Sprague-Dawley rats (n = 105) were fed either LF (low-fat) or MHF (moderately high-fat) diets for 13 weeks before coronary occlusion for 45 min, followed by reperfusion for 60 min. Compared with LF-fed and lean MHF-fed rats, obese MHF-fed rats developed metabolic disturbances similar to those seen in the metabolic syndrome, including being overweight by 24% (compared with lean MHF-fed rats), having 74% more visceral fat (compared with LF-fed rats), 15% higher blood pressure (compared with LF-fed rats), 116% higher plasma insulin (compared with lean MHF-fed rats), 10% higher fasting plasma glucose (compared with LF-fed rats), 35% higher non-fasting plasma glucose (compared with lean MHF-fed rats), 36% higher plasma leptin (compared with lean MHF-fed rats) and a tendency to lower plasma adiponectin and higher plasma non-esterified fatty acids. Infarct size was similar in the three groups of rats (36+/-14, 42+/-18 and 41+/-14% in obese MHF-fed, lean MHF-fed and LF-fed rats respectively). In conclusion, rats fed a MHF diet developed metabolic syndrome, but this did not influence myocardial infarct size. PMID:16448385

  10. Myocardial Oxidative Metabolism and Protein Synthesis during Mechanical Circulatory Support by Extracorporeal Membrane Oxygenation

    SciTech Connect

    Priddy, MD, Colleen M.; Kajimoto, Masaki; Ledee, Dolena; Bouchard, Bertrand; Isern, Nancy G.; Olson, Aaron; Des Rosiers, Christine; Portman, Michael A.

    2013-02-01

    Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support essential for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative. We focused on the amino acid leucine, and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart (i) the fractional contribution of leucine (FcLeucine) and pyruvate (FCpyruvate) to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and (ii) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 hours of normal circulation or ECMO) and intracoronary infusion [13C6,15N]-L-leucine (3.7 mM) alone or with [2-13C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (~ 40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. Conclusion: The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining (i) metabolic flexibility indicated by ability to respond to pyruvate, and (ii) a normal or increased capacity for global protein synthesis, suggesting an improved protein balance.

  11. Mangiferin protect myocardial insults through modulation of MAPK/TGF-β pathways.

    PubMed

    Suchal, Kapil; Malik, Salma; Gamad, Nanda; Malhotra, Rajiv Kumar; Goyal, Sameer N; Ojha, Shreesh; Kumari, Santosh; Bhatia, Jagriti; Arya, Dharamvir Singh

    2016-04-01

    Mangiferin, a xanthone glycoside isolated from leaves of Mangifera indica (Anacardiaceae) is known to modulate many biological targets in inflammation and oxidative stress. The present study was designed to investigate whether mangiferin exerts protection against myocardial ischemia-reperfusion (IR) injury and possible role of Mitogen Activated Protein Kinase (MAPKs) and Transforming Growth Factor-β (TGF-β) pathways in its cardioprotection. Male albino Wistar rats were treated with mangiferin (40 mg/kg, i.p.) for 15 days. At the end of the treatment protocol, rats were subjected to IR injury consisting of 45 min ischemia followed by 1h reperfusion. IR-control rats caused significant cardiac dysfunction, increased serum cardiac injury markers, lipid peroxidation and a significant decrease in tissue antioxidants as compared to sham group. Histopathological examination of IR rats revealed myocardial necrosis, edema and infiltration of inflammatory cells. However, pretreatment with mangiferin significantly restored myocardial oxidant-antioxidant status, maintained membrane integrity, and attenuated the levels of proinflammatory cytokines, pro-apoptotic proteins and TGF-β. Furthermore, mangiferin significantly reduced the phosphorylation of p38, and JNK and enhanced phosphorylation of ERK1/2. These results suggest that mangiferin protects against myocardial IR injury by modulating MAPK mediated inflammation and apoptosis. PMID:26921754

  12. Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy.

    PubMed

    Yipintsoi, Tada; Kroll, Keith; Bassingthwaighte, James B

    2016-02-01

    Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs. local vasomotion, coronary flows were increased in open-chest dogs by stimulating myocardial metabolism (catecholamines + atropine) with and without adenosine. During control states mean left ventricular (LV) myocardial blood flows (microspheres) were 0.5-1 ml·g(-1)·min(-1) and increased to 2-3 ml·g(-1)·min(-1) with catecholamine infusion and to ∼4 ml·g(-1)·min(-1) with adenosine (Ado). Flow heterogeneity was similar in all states: relative dispersion (RD = SD/mean) was ∼25%, using LV pieces 0.1-0.2% of total. During catecholamine infusion local flows increased in proportion to the mean flows in 45% of the LV, "tracking" closely (increased proportionately to mean flow), while ∼40% trended toward the mean. Near-neighbor regional flows remained strongly spatially correlated, with fractal dimension D near 1.2 (Hurst coefficient 0.8). The spatial patterns remain similar at varied levels of metabolic stimulation inferring metabolic dominance. In contrast, adenosine vasodilation increased flows eightfold times control while destroying correlation with the control state. The Ado-induced spatial patterns differed from control but were self-consistent, inferring that with full vasodilation the relaxed arterial anatomy dominates the distribution. We conclude that vascular anatomy governs flow distributions during adenosine vasodilation but that metabolic vasoregulation dominates in normal physiological states. PMID:26589329

  13. HDAC Inhibition Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy.

    PubMed

    Lee, Ting-I; Kao, Yu-Hsun; Tsai, Wen-Chin; Chung, Cheng-Chih; Chen, Yao-Chang; Chen, Yi-Jen

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) regulate cardiac glucose and lipid homeostasis. Histone deacetylase (HDAC) inhibitor has anti-inflammatory effects which may play a key role in modulating PPARs and fatty acid metabolism. The aim of this study was to investigate whether HDAC inhibitor, MPT0E014, can modulate myocardial PPARs, inflammation, and fatty acid metabolism in diabetes mellitus (DM) cardiomyopathy. Electrocardiography, echocardiography, and western blotting were used to evaluate the electrophysiological activity, cardiac structure, fatty acid metabolism, inflammation, and PPAR isoform expressions in the control and streptozotocin-nicotinamide-induced DM rats with or without MPT0E014. Compared to control, DM and MPT0E014-treated DM rats had elevated blood glucose levels and lower body weights. However, MPT0E014-treated DM and control rats had smaller left ventricular end-diastolic diameter and shorter QT interval than DM rats. The control and MPT0E014-treated DM rats had greater cardiac PPAR-α and PPAR-δ protein expressions, but less cardiac PPAR-γ than DM rats. Moreover, control and MPT0E014-treated DM rats had lower concentrations of 5' adenosine monophosphate-activated protein kinase 2α, PPAR-γ coactivator 1α, phosphorylated acetyl CoA carboxylase, cluster of differentiation 36, diacylglycerol acyltransferase 1 (DGAT1), DGAT2, tumor necrosis factor-α, and interleukin-6 protein than DM rats. HDAC inhibition significantly attenuated DM cardiomyopathy through modulation of cardiac PPARS, fatty acid metabolism, and proinflammatory cytokines. PMID:27446205

  14. Deoxyglucose method for the estimation of local myocardial glucose metabolism with positron computed tomography

    SciTech Connect

    Ratib, O.; Phelps, M.E.; Huang, S.C.; Henze, E.; Selin, C.E.; Schelbert, H.R.

    1981-01-01

    The deoxyglucose method originally developed for measurements of the local cerebral metabolic rate for glucose has been investigated in terms of its application to studies of the heart with positron computed tomography (PCT) and FDG. Studies were performed in dogs to measure the tissue kinetics of FDG with PCT and by direct arterial-venous sampling. The operational equation developed in our laboratory as an extension of the Sokoloff model was used to analyze the data. The FDG method accurately predicted the true MMRGlc even when the glucose metabolic rate was normal but myocardial blood flow (MBF) was elevated 5 times the control value or when metabolism was reduced to 10% of normal and MBF increased 5 times normal. Improvements in PCT resolution are required to improve the accuracy of the estimates of the rate constants and the MMRGlc.

  15. Myocardial metabolism of pantothenic acid in chronically diabetic rats.

    PubMed

    Beinlich, C J; Naumovitz, R D; Song, W O; Neely, J R

    1990-03-01

    Transport and metabolism of [3H]pantothenic acid ([3H]Pa) was investigated in hearts from control and streptozotocin-induced diabetic rats. In isolated perfused hearts from control animals, the transport of [3H]Pa was linear over 3 h of perfusion when 11 mM glucose was the only exogenous substrate. The in vitro transport of [3H]Pa by hearts from 48-h diabetic rats was reduced by 65% compared to controls and was linear over 2 h of perfusion with no further accumulation of Pa during the third hour. The defect in transport observed in vitro could be corrected by in vivo treatment with 4 U Lente insulin/day for 2 days. In vitro addition of insulin in the presence of 11 mM glucose or 11 mM glucose plus 1.2 mM palmitate had no effect on [3H]Pa transport in hearts from 48-h diabetic rats during 3 h of perfusion. Accumulation of [3H]Pa was not inhibited by inclusion of 0.7 mM amino acids, 1 mM carnitine, 50 microM mersalic acid or 1 mM panthenol, pantoyllactone or pantoyltaurine. Uptake was inhibited by 1 mM nonanoic, octanoic or heptanoic acid, 0.1 mM biotin or 0.25 mM probenecid, suggesting a requirement for the terminal carboxyl group for transport. Transport of pantothenic acid was reduced in hearts from diabetic rats within 24 h of injection of streptozotocin. In vitro accumulation of [3H]Pa decreased to 10% of control 1 week after streptozotocin injection and then remained at 30% of the control value over 10 weeks.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2141362

  16. HDAC Inhibition Elicits Myocardial Protective Effect through Modulation of MKK3/Akt-1

    PubMed Central

    Zhao, Ting C.; Du, Jianfeng; Zhuang, Shugang; Liu, Paul; Zhang, Ling X.

    2013-01-01

    We and others have demonstrated that HDAC inhibition protects the heart against myocardial injury. It is known that Akt-1 and MAP kinase play an essential role in modulation of myocardial protection and cardiac preconditioning. Our recent observations have shown that Akt-1 was activated in post-myocardial infarction following HDAC inhibition. However, it remains unknown whether MKK3 and Akt-1 are involved in HDAC inhibition-induced myocardial protection in acute myocardial ischemia and reperfusion injury. We sought to investigate whether the genetic disruption of Akt-1 and MKK3 eliminate cardioprotection elicited by HDAC inhibition and whether Akt-1 is associated with MKK3 to ultimately achieve protective effects. Adult wild type and MKK3−/−, Akt-1−/− mice received intraperitoneal injections of trichostatin A (0.1mg/kg), a potent inhibitor of HDACs. The hearts were subjected to 30 min myocardial ischemia/30 min reperfusion in the Langendorff perfused heart after twenty four hours to elicit pharmacologic preconditioning. Left ventricular function was measured, and infarct size was determined. Acetylation and phosphorylation of MKK3 were detected and disruption of Akt-1 abolished both acetylation and phosphorylation of MKK3. HDAC inhibition produces an improvement in left ventricular functional recovery, but these effects were abrogated by disruption of either Akt-1 or MKK3. Disruption of Akt-1 or MKK3 abolished the effects of HDAC inhibition-induced reduction of infarct size. Trichostatin A treatment resulted in an increase in MKK3 phosphorylation or acetylation in myocardium. Taken together, these results indicate that stimulation of the MKK3 and Akt-1 pathway is a novel approach to HDAC inhibition -induced cardioprotection. PMID:23762381

  17. Snail modulates cell metabolism in MDCK cells

    SciTech Connect

    Haraguchi, Misako; Indo, Hiroko P.; Iwasaki, Yasumasa; Iwashita, Yoichiro; Fukushige, Tomoko; Majima, Hideyuki J.; Izumo, Kimiko; Horiuchi, Masahisa; Kanekura, Takuro; Furukawa, Tatsuhiko; Ozawa, Masayuki

    2013-03-22

    Highlights: ► MDCK/snail cells were more sensitive to glucose deprivation than MDCK/neo cells. ► MDCK/snail cells had decreased oxidative phosphorylation, O{sub 2} consumption and ATP content. ► TCA cycle enzyme activity, but not expression, was lower in MDCK/snail cells. ► MDCK/snail cells showed reduced PDH activity and increased PDK1 expression. ► MDCK/snail cells showed reduced expression of GLS2 and ACLY. -- Abstract: Snail, a repressor of E-cadherin gene transcription, induces epithelial-to-mesenchymal transition and is involved in tumor progression. Snail also mediates resistance to cell death induced by serum depletion. By contrast, we observed that snail-expressing MDCK (MDCK/snail) cells undergo cell death at a higher rate than control (MDCK/neo) cells in low-glucose medium. Therefore, we investigated whether snail expression influences cell metabolism in MDCK cells. Although gylcolysis was not affected in MDCK/snail cells, they did exhibit reduced pyruvate dehydrogenase (PDH) activity, which controls pyruvate entry into the tricarboxylic acid (TCA) cycle. Indeed, the activity of multiple enzymes involved in the TCA cycle was decreased in MDCK/snail cells, including that of mitochondrial NADP{sup +}-dependent isocitrate dehydrogenase (IDH2), succinate dehydrogenase (SDH), and electron transport Complex II and Complex IV. Consequently, lower ATP content, lower oxygen consumption and increased survival under hypoxic conditions was also observed in MDCK/snail cells compared to MDCK/neo cells. In addition, the expression and promoter activity of pyruvate dehydrogenase kinase 1 (PDK1), which phosphorylates and inhibits the activity of PDH, was increased in MDCK/snail cells, while expression levels of glutaminase 2 (GLS2) and ATP-citrate lyase (ACLY), which are involved in glutaminolysis and fatty acid synthesis, were decreased in MDCK/snail cells. These results suggest that snail modulates cell metabolism by altering the expression and activity of

  18. Alterations in myocardial energy metabolism induced by the anti-cancer drug doxorubicin.

    PubMed

    Tokarska-Schlattner, Malgorzata; Wallimann, Theo; Schlattner, Uwe

    2006-09-01

    Doxorubicin and other anthracyclines are among the most potent chemotherapeutic drugs for the treatment of acute leukaemia, lymphomas and different types of solid tumours such as breast, liver and lung cancers. Their clinical use is, however, limited by the risk of severe cardiotoxicity, which can lead to irreversible congestive heart failure. There is increasing evidence that essential components of myocardial energy metabolism are among the highly sensitive and early targets of doxorubicin-induced damage. Here we review doxorubicin-induced detrimental changes in cardiac energetics, with an emphasis on the emerging importance of defects in energy-transferring and -signalling systems, like creatine kinase and AMP-activated protein kinase. PMID:16945832

  19. Myocardial protection during aortic valve replacement. Cardiac metabolism and enzyme release following hypothermic cardioplegia.

    PubMed

    Bomfim, V; Kaijser, L; Bendz, R; Sylvén, C; Olin, C

    1980-01-01

    Cardiac metabolism following hypothermic potassium cardioplegia was studied in 23 patients undergoing isolated aortic valve replacement. All had normal coronary arteries. Cardioplegia was induced by infusing 700-1 000 ml of cold Ringer's acetate containing 20 mekv K+ selectively into the left coronary artery. Simultaneous blood samples were taken from the radial artery, a central vein and from the coronary sinus before and after cardioplegia. The PO2, O2-saturation and content, PCO2, pH, lactate, glucose, potassium, myoglobin, total creatine kinase (CK), its isoenzyme CK-MB, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were assessed. Before bypass lactate was extracted by the heart. During the initial 10 to 20 min after cardioplegia there was a marked release of lactate in the coronary sinus. Myoglobin concentration and CK-MB serum activity peaked during the first 4 hours after the release of the aortic cross-clamping. In order to determine the best indicator of myocardial damage after cardioplegia, duration of extracorporeal circulation (ECC-time), aortic occlusion time (AOT), mean myocardial temperature (MMT) and the product of AOT and MMT, referred to as time-temperature area (TTA), were related to possible indicators of myocardial injury, such as enzyme and myoglobin release. The TTA was the best way of expressing the degree of exposure of the heart to ischaemia. The CK-MB to peak area (CK-MB max area) was the best indicator of the degree of ischaemic injury sustained by the heart during operation. PMID:7375890

  20. Adaptation of myocardial blood flow to increased metabolic demand is not dependent on endothelial vasodilators in the rat heart.

    PubMed Central

    Tiefenbacher, C. P.; Tillmanns, H.; Niroomand, F.; Zimmermann, R.; Kübler, W.

    1997-01-01

    OBJECTIVE: To investigate the role of endothelial vasodilating factors in adaptation of myocardial blood flow to increased metabolic demands. DESIGN: Alterations in the effects of endothelium dependent (acetylcholine) and independent (sodium nitroprusside) vasodilators and the beta 1 receptor agonist dobutamine were studied after inhibition of endothelium derived relaxing factor (EDRF) with L-NG-nitro-arginine methyl ester (L-NAME), prostanoid synthesis with indomethacin, and ATP sensitive potassium channels with glibenclamide. EXPERIMENTAL ANIMALS: Female Wistar rats, in situ perfused heart. MAIN OUTCOME MEASURES: Myocardial blood flow (H2 clearance); systolic fractional thickening (pulsed Doppler); mean arterial blood pressure. RESULTS: L-NAME reduced myocardial blood flow by 58 (12)% (mean (SD), P < 0.001) and systolic thickening fraction (FT) by 36 (9)% (P < 0.05). These effects were significantly reversed by administration of L-arginine but not D-arginine. Pretreatment with L-NAME inhibited the increase in myocardial blood flow caused by acetylcholine (control: +42 (9)%; L-NAME: -29 (7)%, P < 0.001) but did not affect the increase in myocardial blood flow caused by sodium nitroprusside (control: +44 (5)%; L-NAME: +34 (10)%, NS). Pretreatment with L-NAME did not change the effect of dobutamine on myocardial blood flow (+61 (3)%) and FT (+32 (8)%) compared with baseline values (P < 0.001). Neither pretreatment with indomethacin nor with glibenclamide reduced the dobutamine induced increase in myocardial blood flow. CONCLUSIONS: Inhibition of EDRF, prostanoid synthesis, and ATP sensitive potassium channels did not reduce the vasodilator reserve during increased metabolic demands induced by beta 1 adrenergic stimulation. Therefore, adaptation of myocardial blood flow to increased metabolic demands is independent of endothelial relaxing factors in the rat heart. PMID:9068398

  1. Exercise and nutrition in myocardial matrix metabolism, remodeling, regeneration, epigenetics, microcirculation, and muscle.

    PubMed

    Tyagi, Suresh C; Joshua, Irving G

    2014-07-01

    Remodeling and myocardial matrix metabolism contributes to cardiac endothelium-myocyte (perivascular fibrosis), myocyte-myocyte (interstitial fibrosis), and mitochondrion-myocyte (fusion and fission) coupling. Matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases (TIMPs) play differential roles in different tissues and diseases. For example, although present in the heart, MMP-3 is known as stromelysin (i.e., stromal tissue enzyme). Interestingly, TIMP-3 causes apoptosis. Exercise and nutrition are synergistic in the mitigation of diseases: exercise releases exosomes containing miRNAs. Nutrition/vitamins B6 and B12 regulate the metabolism of homocysteine (an epigenetic byproduct of DNA/RNA/protein methylation). Thus, epigenetic silencing is an important therapeutic target. The statistical analysis of cohorts may be less indicative for the treatment of a disease, particularly if the 2 twins are different in terms of responding to the medicine for the same disease, therefore, personalized medicine is the future of therapy. PMID:24959992

  2. Targeting myocardial substrate metabolism in heart failure: potential for new therapies

    PubMed Central

    Ardehali, Hossein; Sabbah, Hani N.; Burke, Michael A.; Sarma, Satyam; Liu, Peter P.; Cleland, John G.F.; Maggioni, Aldo; Fonarow, Gregg C.; Abel, E. Dale; Campia, Umberto; Gheorghiade, Mihai

    2012-01-01

    The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area. PMID:22253453

  3. Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation

    PubMed Central

    Crawford, Peter A.; Crowley, Jan R.; Sambandam, Nandakumar; Muegge, Brian D.; Costello, Elizabeth K.; Hamady, Micah; Knight, Rob; Gordon, Jeffrey I.

    2009-01-01

    Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a gut microbiota transplant from conventionally raised donors were compared in the fed and fasted states by using functional genomic, biochemical, and physiologic assays. A 24-h fast produces a marked change in gut microbial ecology. Short-chain fatty acids generated from microbial fermentation of available glycans are maintained at higher levels compared with GF controls. During fasting, a microbiota-dependent, Pparα-regulated increase in hepatic ketogenesis occurs, and myocardial metabolism is directed to ketone body utilization. Analyses of heart rate, hydraulic work, and output, mitochondrial morphology, number, and respiration, plus ketone body, fatty acid, and glucose oxidation in isolated perfused working hearts from GF and colonized animals (combined with in vivo assessments of myocardial physiology) revealed that the fasted GF heart is able to sustain its performance by increasing glucose utilization, but heart weight, measured echocardiographically or as wet mass and normalized to tibial length or lean body weight, is significantly reduced in both fasted and fed mice. This myocardial-mass phenotype is completely reversed in GF mice by consumption of a ketogenic diet. Together, these results illustrate benefits provided by the gut microbiota during periods of nutrient deprivation, and emphasize the importance of further exploring the relationship between gut microbes and cardiovascular health. PMID:19549860

  4. The haemodynamic and metabolic effects of tolmesoxide with special reference to impaired myocardial function.

    PubMed Central

    Mackenzie, J. E.; Marshall, R. J.; Parratt, J. R.

    1986-01-01

    The haemodynamic, metabolic and regional blood flow effects of the vasodilator, tolmesoxide (1 mg kg-1 min-1 for 20 min by intravenous infusion) were examined in two groups of greyhound dogs anaesthetized with alpha-chloralose and mechanically ventilated. One group of dogs was thoracotomized and subjected to acute coronary artery occlusion. In these dogs tolmesoxide was infused 2.5 h after occlusion when there was evidence of impaired myocardial function. Tolmesoxide administration resulted in marked systemic hypotension which was associated with myocardial stimulation (increase in heart rate and LVdP/dtmax). These effects were less marked in thoracotomized dogs subjected to coronary artery occlusion. Cardiac stimulation was attenuated by pretreatment with the beta-adrenoceptor antagonist, atenolol. Peripheral resistance and left ventricular end-diastolic pressure (LVEDP) were reduced by tolmesoxide. In spite of the systemic hypotension, the marked reduction in LVEDP resulted in an enhanced subendocardial driving pressure and an increased blood flow to ischaemic regions of the left ventricular wall as measured with Xe133 clearance. Blood flow to normal regions of the left ventricular wall was also increased by tolmesoxide. A metabolic and respiratory acidosis may have contributed to the haemodynamic effects of tolmesoxide. Plasma renin levels were significantly elevated by the drug. Tolmesoxide administration thus resulted in cardiac stimulation, reduced both pre-load and after-load, yet maintained coronary and pulmonary perfusion. This haemodynamic profile of tolmesoxide would explain the beneficial effects obtained with this drug in the treatment of cardiac failure. PMID:3779213

  5. Changes in metabolic modules under environmental variations

    NASA Astrophysics Data System (ADS)

    Almaas, Eivind

    2006-03-01

    During the last few years, network approaches have shown great promise as a tool to both analyze and provide understanding of complex systems as disparate as the world-wide web and cellular metabolism. Much effort has been focused on characterizing topological properties of such systems. However, in order to develop detailed descriptions of complex networks, we need to look beyond their topology and incorporate dynamical aspects. The cellular metabolism, where nodes correspond to metabolites and links indicate chemical reactions, is an excellent model system where theoretical predictions can be compared with experimental results. I will present recent insights into the principles governing the modular utilization of the cellular metabolism [1,2,3]. We find that, while most metabolic reactions have small fluxes, the metabolism's activity is dominated by an interconnected sub-network of reactions with very high fluxes [1]. For the bacteria H. pylori and E. coli and the yeast S. cerevisiae, the metabolism responds to changes in growth conditions by reorganizing the rates of select reactions predominantly within this high-flux backbone. Furthermore, these networks are organized around the metabolic core -- a set of reactions that are always in use [2]. Strikingly, the activity of the metabolic core reactions is highly synchronized, and the core reactions are significantly more essential and evolutionary conserved than the non-core ones. [1] E. Almaas, B. Kovacs, T. Vicsek, Z.N. Oltvai and A.-L. Barabasi. Nature 427, 839 (2004). [2] E. Almaas, Z.N. Oltvai and A.-L. Barabasi. PLoS Comput. Biol. In press (2005). 10.1371/journal.pcbi.0010068.eor [3] P.J. Macdonald, E. Almaas and A.-L. Barabasi. Europhys. Lett. 72, 308 (2005).

  6. Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis

    PubMed Central

    2011-01-01

    Background In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC. Methods Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11C-glucose and 11C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography. Results Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/μU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/μU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001). Conclusion Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for

  7. Normalizing the metabolic phenotype after myocardial infarction; impact of subchronic high fat feeding

    PubMed Central

    Berthiaume, Jessica M.; Young, Martin E.; Chen, Xiaoqin; McElfresh, Tracy A.; Yu, Xin; Chandler, Margaret P.

    2012-01-01

    The normal heart relies primarily on the oxidation of fatty acids (FA) for ATP production, whereas during heart failure (HF) glucose utilization increases, implying pathological changes to cardiac energy metabolism. Despite the noted lipotoxic effects of elevating FA, our work has demonstrated a cardioprotective effect of a high fat diet (SAT) when fed after myocardial infarction (MI), as compared to normal chow (NC) fed cohorts. This data has suggested a mechanistic link to energy metabolism. The goal of this study was to determine the impact of SAT on the metabolic phenotype of the heart after MI. Male Wistar rats underwent coronary ligation surgery (MI) and were evaluated after 8 weeks of SAT. Induction of MI was verified by echocardiography. LV function assessed by in vivo hemodynamic measurements revealed improvements in the MI-SAT group as compared to MI-NC. Perfused working hearts revealed a decrease in cardiac work in MI-NC that was improved in MI-SAT. Glucose oxidation was increased and FA oxidation decreased in MINC compared to shams suggesting an alteration in the metabolic profile that was ameliorated by SAT. 31P NMR analysis of Langendorff perfused hearts revealed no differences in PCr:ATP indicating no overt energy deficit in MI groups. Phospho-PDH and PDK4 were increased in MI-SAT, consistent with a shift towards fatty acid oxidation (FAO). Overall, these results support the hypothesis that SAT post-infarction promotes a normal metabolic phenotype that may serve a cardioprotective role in the injured heart. PMID:22542451

  8. Control of intraoperative hypertension with isoflurane in patients with coronary artery disease: effects on regional myocardial blood flow and metabolism.

    PubMed

    Sahlman, L; Milocco, I; Appelgren, L; William-Olsson, G; Ricksten, S E

    1989-02-01

    The effect of isoflurane on regional myocardial metabolism and blood flow, when used as an adjunct to fentanyl-nitrous oxide anesthesia, to control intraoperative hypertension was investigated. Twenty-two patients with two- or three-vessel coronary artery disease with an ejection fraction greater than 0.5 and on beta-blockers up to the morning of surgery were studied during elective coronary artery by-pass grafting. Systemic and pulmonary hemodynamics, and regional (great cardiac vein, GCVF) myocardial blood flow and myocardial metabolic parameters were measured. In 10 patients, both GCVF and global (coronary sinus, CSF) myocardial blood flows were recorded. Measurements were made 1) after induction of anesthesia but prior to skin incision, 2) during sternotomy, and 3) during isoflurane administration after its use to reduce arterial pressure to the presternotomy level. The increase in systemic arterial pressure during sternotomy was due to an increase in systemic vascular resistance accompanied by increases in heart rate, pulmonary capillary wedge pressure, (PCWP) regional myocardial oxygen consumption and extraction, GCVF and total coronary vascular resistance. Isoflurane reduced systemic arterial pressure but not PCWP, to presternotomy levels within 6.9 +/- 0.7 minutes at an end-tidal concentration of 1.5 +/- 0.2%. Isoflurane induced a pronounced systemic and coronary vasodilatation and increases in cardiac index, heart rate and regional myocardial oxygen extraction while the GCVF/CSF ratio remained unchanged. While mean regional--MLE% values were not effected by sternotomy, in two patients myocardial lactate production was seen during sternotomy but not during isoflurane. In another two patients, isoflurane induced lactate production.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2783640

  9. HDAC Inhibition Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy

    PubMed Central

    Lee, Ting-I; Tsai, Wen-Chin; Chung, Cheng-Chih; Chen, Yao-Chang; Chen, Yi-Jen

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) regulate cardiac glucose and lipid homeostasis. Histone deacetylase (HDAC) inhibitor has anti-inflammatory effects which may play a key role in modulating PPARs and fatty acid metabolism. The aim of this study was to investigate whether HDAC inhibitor, MPT0E014, can modulate myocardial PPARs, inflammation, and fatty acid metabolism in diabetes mellitus (DM) cardiomyopathy. Electrocardiography, echocardiography, and western blotting were used to evaluate the electrophysiological activity, cardiac structure, fatty acid metabolism, inflammation, and PPAR isoform expressions in the control and streptozotocin-nicotinamide-induced DM rats with or without MPT0E014. Compared to control, DM and MPT0E014-treated DM rats had elevated blood glucose levels and lower body weights. However, MPT0E014-treated DM and control rats had smaller left ventricular end-diastolic diameter and shorter QT interval than DM rats. The control and MPT0E014-treated DM rats had greater cardiac PPAR-α and PPAR-δ protein expressions, but less cardiac PPAR-γ than DM rats. Moreover, control and MPT0E014-treated DM rats had lower concentrations of 5′ adenosine monophosphate-activated protein kinase 2α, PPAR-γ coactivator 1α, phosphorylated acetyl CoA carboxylase, cluster of differentiation 36, diacylglycerol acyltransferase 1 (DGAT1), DGAT2, tumor necrosis factor-α, and interleukin-6 protein than DM rats. HDAC inhibition significantly attenuated DM cardiomyopathy through modulation of cardiac PPARS, fatty acid metabolism, and proinflammatory cytokines. PMID:27446205

  10. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction

    PubMed Central

    Ali, Safina; Ussher, John R.; Baggio, Laurie L.; Kabir, M. Golam; Charron, Maureen J.; Ilkayeva, Olga; Newgard, Christopher B.; Drucker, Daniel J.

    2014-01-01

    Objective Glucagon is a hormone with metabolic actions that maintains normoglycemia during the fasting state. Strategies enabling either inhibition or activation of glucagon receptor (Gcgr) signaling are being explored for the treatment of diabetes or obesity. However, the cardiovascular consequences of manipulating glucagon action are poorly understood. Methods We assessed infarct size and the following outcomes following left anterior descending (LAD) coronary artery ligation; cardiac gene and protein expression, acylcarnitine profiles, and cardiomyocyte survival in normoglycemic non-obese wildtype mice, and in newly generated mice with selective inactivation of the cardiomyocyte Gcgr. Complementary experiments analyzed Gcgr signaling and cell survival in cardiomyocyte cultures and cell lines, in the presence or absence of exogenous glucagon. Results Exogenous glucagon administration directly impaired recovery of ventricular pressure in ischemic mouse hearts ex vivo, and increased mortality from myocardial infarction after LAD coronary artery ligation in mice in a p38 MAPK-dependent manner. In contrast, cardiomyocyte-specific reduction of glucagon action in adult GcgrCM−/− mice significantly improved survival, and reduced hypertrophy and infarct size following myocardial infarction. Metabolic profiling of hearts from GcgrCM−/− mice revealed a marked reduction in long chain acylcarnitines in both aerobic and ischemic hearts, and following high fat feeding, consistent with an essential role for Gcgr signaling in the control of cardiac fatty acid utilization. Conclusions Activation or reduction of cardiac Gcgr signaling in the ischemic heart produces substantial cardiac phenotypes, findings with implications for therapeutic strategies designed to augment or inhibit Gcgr signaling for the treatment of metabolic disorders. PMID:25685700

  11. Potassium Uptake Modulates Staphylococcus aureus Metabolism.

    PubMed

    Gries, Casey M; Sadykov, Marat R; Bulock, Logan L; Chaudhari, Sujata S; Thomas, Vinai C; Bose, Jeffrey L; Bayles, Kenneth W

    2016-01-01

    As a leading cause of community-associated and nosocomial infections, Staphylococcus aureus requires sophisticated mechanisms that function to maintain cellular homeostasis in response to its exposure to changing environmental conditions. The adaptation to stress and maintenance of homeostasis depend largely on membrane activity, including supporting electrochemical gradients and synthesis of ATP. This is largely achieved through potassium (K(+)) transport, which plays an essential role in maintaining chemiosmotic homeostasis, affects antimicrobial resistance, and contributes to fitness in vivo. Here, we report that S. aureus Ktr-mediated K(+) uptake is necessary for maintaining cytoplasmic pH and the establishment of a proton motive force. Metabolite analyses revealed that K(+) deficiency affects both metabolic and energy states of S. aureus by impairing oxidative phosphorylation and directing carbon flux toward substrate-level phosphorylation. Taken together, these results underline the importance of K(+) uptake in maintaining essential components of S. aureus metabolism. IMPORTANCE Previous studies describing mechanisms for K(+) uptake in S. aureus revealed that the Ktr-mediated K(+) transport system was required for normal growth under alkaline conditions but not under neutral or acidic conditions. This work focuses on the effect of K(+) uptake on S. aureus metabolism, including intracellular pH and carbon flux, and is the first to utilize a pH-dependent green fluorescent protein (GFP) to measure S. aureus cytoplasmic pH. These studies highlight the role of K(+) uptake in supporting proton efflux under alkaline conditions and uncover a critical role for K(+) uptake in establishing efficient carbon utilization. PMID:27340697

  12. Potassium Uptake Modulates Staphylococcus aureus Metabolism

    PubMed Central

    Gries, Casey M.; Sadykov, Marat R.; Bulock, Logan L.; Chaudhari, Sujata S.; Thomas, Vinai C.; Bose, Jeffrey L.

    2016-01-01

    ABSTRACT As a leading cause of community-associated and nosocomial infections, Staphylococcus aureus requires sophisticated mechanisms that function to maintain cellular homeostasis in response to its exposure to changing environmental conditions. The adaptation to stress and maintenance of homeostasis depend largely on membrane activity, including supporting electrochemical gradients and synthesis of ATP. This is largely achieved through potassium (K+) transport, which plays an essential role in maintaining chemiosmotic homeostasis, affects antimicrobial resistance, and contributes to fitness in vivo. Here, we report that S. aureus Ktr-mediated K+ uptake is necessary for maintaining cytoplasmic pH and the establishment of a proton motive force. Metabolite analyses revealed that K+ deficiency affects both metabolic and energy states of S. aureus by impairing oxidative phosphorylation and directing carbon flux toward substrate-level phosphorylation. Taken together, these results underline the importance of K+ uptake in maintaining essential components of S. aureus metabolism. IMPORTANCE Previous studies describing mechanisms for K+ uptake in S. aureus revealed that the Ktr-mediated K+ transport system was required for normal growth under alkaline conditions but not under neutral or acidic conditions. This work focuses on the effect of K+ uptake on S. aureus metabolism, including intracellular pH and carbon flux, and is the first to utilize a pH-dependent green fluorescent protein (GFP) to measure S. aureus cytoplasmic pH. These studies highlight the role of K+ uptake in supporting proton efflux under alkaline conditions and uncover a critical role for K+ uptake in establishing efficient carbon utilization. PMID:27340697

  13. Trenbolone Improves Cardiometabolic Risk Factors and Myocardial Tolerance to Ischemia-Reperfusion in Male Rats With Testosterone-Deficient Metabolic Syndrome.

    PubMed

    Donner, Daniel G; Elliott, Grace E; Beck, Belinda R; Bulmer, Andrew C; Lam, Alfred K; Headrick, John P; Du Toit, Eugene F

    2016-01-01

    The increasing prevalence of obesity adds another dimension to the pathophysiology of testosterone (TEST) deficiency (TD) and potentially impairs the therapeutic efficacy of classical TEST replacement therapy. We investigated the therapeutic effects of selective androgen receptor modulation with trenbolone (TREN) in a model of TD with the metabolic syndrome (MetS). Male Wistar rats (n=50) were fed either a control standard rat chow (CTRL) or a high-fat/high-sucrose (HF/HS) diet. After 8 weeks of feeding, rats underwent sham surgery or an orchiectomy (ORX). Alzet miniosmotic pumps containing either vehicle, 2-mg/kg·d TEST or 2-mg/kg·d TREN were implanted in HF/HS+ORX rats. Body composition, fat distribution, lipid profile, and insulin sensitivity were assessed. Infarct size was quantified to assess myocardial damage after in vivo ischaemia reperfusion, before cardiac and prostate histology was performed. The HF/HS+ORX animals had increased sc and visceral adiposity; circulating triglycerides, cholesterol, and insulin; and myocardial damage, with low circulating TEST compared with CTRLs. Both TEST and TREN protected HF/HS+ORX animals against sc fat accumulation, hypercholesterolaemia, and myocardial damage. However, only TREN protected against visceral fat accumulation, hypertriglyceridaemia, and hyperinsulinaemia and reduced myocardial damage relative to CTRLs. TEST caused widespread cardiac fibrosis and prostate hyperplasia, which were less pronounced with TREN. We propose that TEST replacement therapy may have contraindications for males with TD and obesity-related MetS. TREN treatment may be more effective in restoring androgen status and reducing cardiovascular risk in males with TD and MetS. PMID:26584015

  14. Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice.

    PubMed

    Peliciari-Garcia, Rodrigo A; Goel, Mehak; Aristorenas, Jonathan A; Shah, Krishna; He, Lan; Yang, Qinglin; Shalev, Anath; Bailey, Shannon M; Prabhu, Sumanth D; Chatham, John C; Gamble, Karen L; Young, Martin E

    2016-10-01

    A mismatch between fatty acid availability and utilization leads to cellular/organ dysfunction during cardiometabolic disease states (e.g., obesity, diabetes mellitus). This can precipitate cardiac dysfunction. The heart adapts to increased fatty acid availability at transcriptional, translational, post-translational and metabolic levels, thereby attenuating cardiomyopathy development. We have previously reported that the cardiomyocyte circadian clock regulates transcriptional responsiveness of the heart to acute increases in fatty acid availability (e.g., short-term fasting). The purpose of the present study was to investigate whether the cardiomyocyte circadian clock plays a role in adaptation of the heart to chronic elevations in fatty acid availability. Fatty acid availability was increased in cardiomyocyte-specific CLOCK mutant (CCM) and wild-type (WT) littermate mice for 9weeks in time-of-day-independent (streptozotocin (STZ) induced diabetes) and dependent (high fat diet meal feeding) manners. Indices of myocardial metabolic adaptation (e.g., substrate reliance perturbations) to STZ-induced diabetes and high fat meal feeding were found to be dependent on genotype. Various transcriptional and post-translational mechanisms were investigated, revealing that Cte1 mRNA induction in the heart during STZ-induced diabetes is attenuated in CCM hearts. At the functional level, time-of-day-dependent high fat meal feeding tended to influence cardiac function to a greater extent in WT versus CCM mice. Collectively, these data suggest that CLOCK (a circadian clock component) is important for metabolic adaption of the heart to prolonged elevations in fatty acid availability. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk. PMID:26721420

  15. Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.

    PubMed Central

    Neubauer, S; Horn, M; Naumann, A; Tian, R; Hu, K; Laser, M; Friedrich, J; Gaudron, P; Schnackerz, K; Ingwall, J S

    1995-01-01

    The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress. PMID:7883957

  16. Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment

    PubMed Central

    Kim, Yong Sook; Jeong, Hye-yun; Kim, Ah Ra; Kim, Woong-Hee; Cho, Haaglim; Um, JungIn; Seo, Youngha; Kang, Wan Seok; Jin, Suk-Won; Kim, Min Chul; Kim, Yong-Chul; Jung, Da-Woon; Williams, Darren R.; Ahn, Youngkeun

    2016-01-01

    The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2′Z,3′E)-6-Bromoindirubin-3′-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti-fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3β inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID:27510556

  17. Myocardial ischemic-reperfusion injury in a rat model of metabolic syndrome.

    PubMed

    Mozaffari, Mahmood S; Schaffer, Stephen W

    2008-10-01

    Hearts of NaCl-induced hypertensive-glucose intolerant (HGI) rats develop reduced infarcts after ischemia-reperfusion injury (IRI) than their hypertensive (H) counterparts. Because high intake of saturated fat is a major risk factor for ischemic heart disease, we tested the hypothesis that chronic (18 weeks) consumption of a high saturated fat diet increases susceptibility to IRI, an effect more marked in the HGI rats than in the H rats. The fat-fed H (HFAT) rat displayed significantly higher body weight and plasma leptin content compared to the H, HGI, or fat-fed HGI (HGIFAT) rats which all showed similar values. In contrast, plasma triglyceride concentration was significantly higher in the HGIFAT rat than in the other three groups. Plasma insulin concentration was similar in the two H groups but higher than that of the two HGI groups. Compared to the H rat, the HGI rat was markedly glucose intolerant, with fat feeding causing comparable worsening of glucose intolerance in each group. The HGIFAT rats displayed a reduction in baseline myocardial contractility and relaxation and a higher end-diastolic pressure compared to the other three groups. Infarct size was significantly lower in the HGI rats than in the H rats. Although fat feeding did not affect infarct size of the H rat, it worsened that of the HGIFAT rat thereby abrogating the differential that existed between the H and HGI rats. In conclusion, excess fat feeding impairs myocardial function of HGI rats and increases their susceptibility to IRI. These findings are of relevance to the metabolic syndrome that manifests as a cluster of insulin resistance, dyslipidemia, and systemic hypertension. PMID:18719642

  18. Analysis of respiratory water--a new method for evaluation of myocardial energy metabolism.

    PubMed

    Schwanke, U; Strauss, H; Arnold, G; Schipke, J D

    1996-11-01

    Aerobic ATP synthesis via oxidative phosphorylation causes a proportional production of respiratory water. Thus the amount of respiratory water produced at a given time should be a reliable measure of the current ATP demand of the mammalian myocardium. Respiratory water from isolated rabbit hearts was labeled by using the stable oxygen isotope 18O. The hearts were perfused according to the method of Langendorff (O. Langendorff. Pfluegers Arch. 61: 291-332, 1895) with 18O2-equilibrated Krebs-Henseleit solution. Control hearts were exclusively perfused with carbogen-equilibrated Krebs-Henseleit solution. Myocardial tissue was then lyophilized; the extracted water and samples from the coronary venous effluent were converted to CO2 by using the guanidine hydrochloride technique. The delta 18O values within the CO2 samples were determined by mass spectrometry and related to the standard mean ocean water (SMOW) scale. Compared with control hearts, the 18O-labeled hearts exhibited a significant increase of delta 18O values from tissue water (-47.50 +/- 0.64 vs. -40.35 +/- 2.05% SMOW; P < 0.05). The values were also significantly increased in the coronary venous effluent after a perfusion time of only 50 s (-47.50 +/- 0.64 vs. -43.66 +/- 0.91% SMOW; P < 0.05). Thus this first adaptation of the guanidine hydrochloride technique on microliter samples of myocardial tissue water and coronary venous effluent demonstrates that this method can be used to evaluate both respiratory activity and the kinetics of cardiac metabolic processes. PMID:8941536

  19. SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM

    PubMed Central

    Nogueiras, Ruben; Habegger, Kirk M.; Chaudhary, Nilika; Finan, Brian; Banks, Alexander S.; Dietrich, Marcelo O.; Horvath, Tamas L.; Sinclair, David A.; Pfluger, Paul T.; Tschöop, Matthias H.

    2013-01-01

    The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD+ levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease. PMID:22811431

  20. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    PubMed

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens. PMID:11265593

  1. Influence of beta-blockers on the myocardial mRNA expressions of circadian clock- and metabolism-related genes.

    PubMed

    Ushijima, Kentarou; Maekawa, Tomohiro; Ishikawa-Kobayashi, Eiko; Ando, Hitoshi; Shiga, Tsuyoshi; Fujimura, Akio

    2013-01-01

    Daily rhythms are regulated by a master clock-system in the suprachiasmatic nucleus and by a peripheral clock-system in each organ. Because norepinephrine is one of the timekeepers for the myocardial circadian clock that influences cardiac metabolism, it is speculated that a beta-blocker may affect the circadian clock and metabolism in heart tissue. In this study, thirty mg/kg/day of propranolol (a lipophilic beta-blocker) or atenolol (a hydrophilic beta-blocker) was given orally to Wistar rats for 4 weeks. The mRNA expressions of Bmal1 and E4BP4 in heart tissue were suppressed by the beta-blockers. However, the mRNA expressions of these clock genes in the suprachiasmatic nucleus were unchanged. Myocardial mRNA expressions of lactate dehydrogenase a and pyruvate dehydrogenase kinase 4 were also suppressed by the beta-blockers. In addition, ATP content in heart tissue was significantly elevated by the beta-blockers throughout 24 hours. The effects of propranolol and atenolol did not differ significantly. This study showed for the first time that a beta-blocker affects myocardial clock gene expression. Propranolol and atenolol increased ATP content in heart tissue throughout 24 hours. The influences of beta-blockers may be negligible on the SCN, and may be independent of lipid solubility on heart tissue. It is well known that these drugs exert a protective effect against myocardial ischemia, which may be mediated by an increase in the preservation of myocardial ATP. PMID:23394803

  2. Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease

    PubMed Central

    Bradley, Jessica M.; Islam, Kazi N.; Polhemus, David J.; Donnarumma, Erminia; Brewster, Luke P.; Tao, Ya-Xiong; Goodchild, Traci T.

    2015-01-01

    Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg·kg−1·day−1 bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation. PMID:25957218

  3. O-GlcNAcylation, Novel Post-Translational Modification Linking Myocardial Metabolism and Cardiomyocyte Circadian Clock*

    PubMed Central

    Durgan, David J.; Pat, Betty M.; Laczy, Boglarka; Bradley, Jerry A.; Tsai, Ju-Yun; Grenett, Maximiliano H.; Ratcliffe, William F.; Brewer, Rachel A.; Nagendran, Jeevan; Villegas-Montoya, Carolina; Zou, Chenhang; Zou, Luyun; Johnson, Russell L.; Dyck, Jason R. B.; Bray, Molly S.; Gamble, Karen L.; Chatham, John C.; Young, Martin E.

    2011-01-01

    The cardiomyocyte circadian clock directly regulates multiple myocardial functions in a time-of-day-dependent manner, including gene expression, metabolism, contractility, and ischemic tolerance. These same biological processes are also directly influenced by modification of proteins by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Because the circadian clock and protein O-GlcNAcylation have common regulatory roles in the heart, we hypothesized that a relationship exists between the two. We report that total cardiac protein O-GlcNAc levels exhibit a diurnal variation in mouse hearts, peaking during the active/awake phase. Genetic ablation of the circadian clock specifically in cardiomyocytes in vivo abolishes diurnal variations in cardiac O-GlcNAc levels. These time-of-day-dependent variations appear to be mediated by clock-dependent regulation of O-GlcNAc transferase and O-GlcNAcase protein levels, glucose metabolism/uptake, and glutamine synthesis in an NAD-independent manner. We also identify the clock component Bmal1 as an O-GlcNAc-modified protein. Increasing protein O-GlcNAcylation (through pharmacological inhibition of O-GlcNAcase) results in diminished Per2 protein levels, time-of-day-dependent induction of bmal1 gene expression, and phase advances in the suprachiasmatic nucleus clock. Collectively, these data suggest that the cardiomyocyte circadian clock increases protein O-GlcNAcylation in the heart during the active/awake phase through coordinated regulation of the hexosamine biosynthetic pathway and that protein O-GlcNAcylation in turn influences the timing of the circadian clock. PMID:22069332

  4. Influence of revascularization on myocardial perfusion, metabolism and function evaluated with I-123-IPPA

    SciTech Connect

    Kropp, J.; Krois, M.; Eichhorn, B.; Feske, W.; Likungu, J.; Kirchhoff, P.J.; Luederitz, B.; Biersack, H.J.; Knapp, F.F. Jr.

    1993-10-01

    Patients with coronary artery disease (CAD) were investigated with sequential SPECT-scintigraphy after administration of 200 MBq of 15-(p-[I-123]iodophenyl)pentadecanoic acid (IPPA) at peak submaximal exercise. Twenty patients underwent coronary angioplasty (PTCA) from which 14 had control coronary arteriography (CA) and left ventricular cineventriculography (LVCV). Nineteen pts underwent bypass graft surgery (ACB) and stress sonagraphy. Semi-quantification of uptake (Up related to perfusion) and turnover (Tr) was obtained by segmental comparison of oblique slices. About 90% of the reperfused myocardial segments in the PTCA-group and 76% in the ACB-group showed an improvement of uptake after therapy (RUp). Of these, 50% and 66% exhibited increased turnover (RTr) after PTCA or ACB. Pathologic RTr was highly correlated with regional wall motion abnormalities after therapy in both groups. In the ACB-group presence of improvement of RTr was correlated with improved RWM at rest and stress. IPPA-studies show potential to provide information about changes of perfusion and metabolism after reperfusion and IPPA-turnover is a good predictor of the pattern of contractile function.

  5. Metabolic Inflammation-Differential Modulation by Dietary Constituents.

    PubMed

    Lyons, Claire L; Kennedy, Elaine B; Roche, Helen M

    2016-01-01

    Obesity arises from a sustained positive energy balance which triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2D. Recent studies, focused on the emerging area of metabolic-inflammation, highlight that specific metabolites can modulate the functional nature and inflammatory phenotype of immune cells. In obesity, expanding adipose tissue attracts immune cells, creating an inflammatory environment within this fatty acid storage organ. Resident immune cells undergo both a pro-inflammatory and metabolic switch in their function. Inflammatory mediators, such as TNF-α and IL-1β, are induced by saturated fatty acids and disrupt insulin signaling. Conversely, monounsaturated and polyunsaturated fatty acids do not interrupt metabolism and inflammation to the same extent. AMPK links inflammation, metabolism and T2D, with roles to play in all and is influenced negatively by obesity. Lipid spillover results in hepatic lipotoxicity and steatosis. Also in skeletal muscle, excessive FFA can impede insulin's action and promote inflammation. Ectopic fat can also affect pancreatic β-cell function, thereby contributing to insulin resistance. Therapeutics, lifestyle changes, supplements and dietary manipulation are all possible avenues to combat metabolic inflammation and the subsequent insulin resistant state which will be explored in the current review. PMID:27128935

  6. Metabolic Inflammation-Differential Modulation by Dietary Constituents

    PubMed Central

    Lyons, Claire L.; Kennedy, Elaine B.; Roche, Helen M.

    2016-01-01

    Obesity arises from a sustained positive energy balance which triggers a pro-inflammatory response, a key contributor to metabolic diseases such as T2D. Recent studies, focused on the emerging area of metabolic-inflammation, highlight that specific metabolites can modulate the functional nature and inflammatory phenotype of immune cells. In obesity, expanding adipose tissue attracts immune cells, creating an inflammatory environment within this fatty acid storage organ. Resident immune cells undergo both a pro-inflammatory and metabolic switch in their function. Inflammatory mediators, such as TNF-α and IL-1β, are induced by saturated fatty acids and disrupt insulin signaling. Conversely, monounsaturated and polyunsaturated fatty acids do not interrupt metabolism and inflammation to the same extent. AMPK links inflammation, metabolism and T2D, with roles to play in all and is influenced negatively by obesity. Lipid spillover results in hepatic lipotoxicity and steatosis. Also in skeletal muscle, excessive FFA can impede insulin’s action and promote inflammation. Ectopic fat can also affect pancreatic β-cell function, thereby contributing to insulin resistance. Therapeutics, lifestyle changes, supplements and dietary manipulation are all possible avenues to combat metabolic inflammation and the subsequent insulin resistant state which will be explored in the current review. PMID:27128935

  7. Comparison between myocardial infarction and diabetes mellitus damage caused angiogenesis or energy metabolism

    PubMed Central

    Li, Chao; Lu, Chengzhi; Zhao, Xiangdong; Chen, Xin

    2015-01-01

    This study aims to compare and analyze lactate dehydrogenase (LDH), succinic dehydrogenase (SDH) and differences in capillary density level in the model of myocardial damage which caused by rats diabetes. The Wistar rats were divided into 4 groups, including control, diabetic, myocardial infarction and two diseases combined group. Ligate descending branch of left coronary artery on 1/3 position or inject streptozotocin into abdominal cavity to establish two kinds of disease models. After 6 w, obtain the myocardial tissues to do the vascular density analysis of tissue sections which are stained and cell tissue enzyme. Explore change of relevant index and differences among groups. Results indicated that degree of LDH and SDH decrease in two kinds of disease model. Compared with control group, level of myocardial vascular of myocardial injury group is higher, and diabetic group is higher than non diabetic group. Quantitative result of FFA in mitochondrial suspension of single disease group is higher than that of control group and two diseases combined group. Level of FFA and LDH of two diseases combined group is consistent with control group. In conclusion, after myocardial damage, which is caused by diabetes mellitus or myocardial infarction, degree of local vascularization increases, diabetes mellitus is more obvious. After myocardial damage, process of myocardial mitochondrial glycolysis and oxidative phosphorylation has some obstacles. But these two kinds of diseases all have cardiac muscle cell which can keep generated procedure of aerobic and anaerobic energy to instead the normal function of cardiac muscle. PMID:26885216

  8. Comparison between myocardial infarction and diabetes mellitus damage caused angiogenesis or energy metabolism.

    PubMed

    Li, Chao; Lu, Chengzhi; Zhao, Xiangdong; Chen, Xin

    2015-01-01

    This study aims to compare and analyze lactate dehydrogenase (LDH), succinic dehydrogenase (SDH) and differences in capillary density level in the model of myocardial damage which caused by rats diabetes. The Wistar rats were divided into 4 groups, including control, diabetic, myocardial infarction and two diseases combined group. Ligate descending branch of left coronary artery on 1/3 position or inject streptozotocin into abdominal cavity to establish two kinds of disease models. After 6 w, obtain the myocardial tissues to do the vascular density analysis of tissue sections which are stained and cell tissue enzyme. Explore change of relevant index and differences among groups. Results indicated that degree of LDH and SDH decrease in two kinds of disease model. Compared with control group, level of myocardial vascular of myocardial injury group is higher, and diabetic group is higher than non diabetic group. Quantitative result of FFA in mitochondrial suspension of single disease group is higher than that of control group and two diseases combined group. Level of FFA and LDH of two diseases combined group is consistent with control group. In conclusion, after myocardial damage, which is caused by diabetes mellitus or myocardial infarction, degree of local vascularization increases, diabetes mellitus is more obvious. After myocardial damage, process of myocardial mitochondrial glycolysis and oxidative phosphorylation has some obstacles. But these two kinds of diseases all have cardiac muscle cell which can keep generated procedure of aerobic and anaerobic energy to instead the normal function of cardiac muscle. PMID:26885216

  9. Chemical modulation of glycerolipid signaling and metabolic pathways

    PubMed Central

    Scott, Sarah A.; Mathews, Thomas P.; Ivanova, Pavlina T.; Lindsley, Craig W.; Brown, H. Alex

    2014-01-01

    Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields—ranging from neuroscience and cancer to diabetes and obesity—have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems. PMID:24440821

  10. Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction.

    PubMed

    Thackeray, James T; Bankstahl, Jens P; Wang, Yong; Wollert, Kai C; Bengel, Frank M

    2016-01-01

    Acute tissue inflammation after myocardial infarction influences healing and remodeling and has been identified as a target for novel therapies. Molecular imaging holds promise for guidance of such therapies. The amino acid (11)C-methionine is a clinically approved agent which is thought to accumulate in macrophages, but not in healthy myocytes. We assessed the suitability of positron emission tomography (PET) with (11)C-methionine for imaging post-MI inflammation, from cell to mouse to man. Uptake assays demonstrated 7-fold higher (11)C-methionine uptake by polarized pro-inflammatory M1 macrophages over anti-inflammatory M2 subtypes (p<0.001). C57Bl/6 mice (n=27) underwent coronary artery ligation or no surgery. Serial (11)C-methionine PET was performed 3, 5 and 7d later. MI mice exhibited a perfusion defect in 32-50% of the left ventricle (LV). PET detected increased (11)C-methionine accumulation in the infarct territory at 3d (5.9±0.9%ID/g vs 4.7±0.9 in remote myocardium, and 2.6±0.5 in healthy mice; p<0.05 and <0.01 respectively), which declined by d7 post-MI (4.3±0.6 in infarct, 3.4±0.8 in remote; p=0.03 vs 3d, p=0.08 vs healthy). Increased (11)C-methionine uptake was associated with macrophage infiltration of damaged myocardium. Treatment with anti-integrin antibodies (anti-CD11a, -CD11b, -CD49d; 100µg) lowered macrophage content by 56% and (11)C-methionine uptake by 46% at 3d post-MI. A patient study at 3d after ST-elevation MI and early reperfusion confirmed elevated (11)C-methionine uptake in the hypoperfused myocardial region. Targeting of elevated amino acid metabolism in pro-inflammatory M1 macrophages enables PET imaging-derived demarcation of tissue inflammation after MI. (11)C-methionine-based molecular imaging may assist in the translation of novel image-guided, inflammation-targeted regenerative therapies. PMID:27570549

  11. Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

    PubMed Central

    Thackeray, James T.; Bankstahl, Jens P.; Wang, Yong; Wollert, Kai C.; Bengel, Frank M.

    2016-01-01

    Acute tissue inflammation after myocardial infarction influences healing and remodeling and has been identified as a target for novel therapies. Molecular imaging holds promise for guidance of such therapies. The amino acid 11C-methionine is a clinically approved agent which is thought to accumulate in macrophages, but not in healthy myocytes. We assessed the suitability of positron emission tomography (PET) with 11C-methionine for imaging post-MI inflammation, from cell to mouse to man. Uptake assays demonstrated 7-fold higher 11C-methionine uptake by polarized pro-inflammatory M1 macrophages over anti-inflammatory M2 subtypes (p<0.001). C57Bl/6 mice (n=27) underwent coronary artery ligation or no surgery. Serial 11C-methionine PET was performed 3, 5 and 7d later. MI mice exhibited a perfusion defect in 32-50% of the left ventricle (LV). PET detected increased 11C-methionine accumulation in the infarct territory at 3d (5.9±0.9%ID/g vs 4.7±0.9 in remote myocardium, and 2.6±0.5 in healthy mice; p<0.05 and <0.01 respectively), which declined by d7 post-MI (4.3±0.6 in infarct, 3.4±0.8 in remote; p=0.03 vs 3d, p=0.08 vs healthy). Increased 11C-methionine uptake was associated with macrophage infiltration of damaged myocardium. Treatment with anti-integrin antibodies (anti-CD11a, -CD11b, -CD49d; 100µg) lowered macrophage content by 56% and 11C-methionine uptake by 46% at 3d post-MI. A patient study at 3d after ST-elevation MI and early reperfusion confirmed elevated 11C-methionine uptake in the hypoperfused myocardial region. Targeting of elevated amino acid metabolism in pro-inflammatory M1 macrophages enables PET imaging-derived demarcation of tissue inflammation after MI. 11C-methionine-based molecular imaging may assist in the translation of novel image-guided, inflammation-targeted regenerative therapies. PMID:27570549

  12. Myocardial metabolism during exposure to carbon monoxide in the conscious dog.

    NASA Technical Reports Server (NTRS)

    Adams, J. D.; Erickson, H. H.; Stone, H. L.

    1973-01-01

    Investigation of the relationship between coronary flow, heart rate, left ventricular function, and myocardial oxygen consumption at increasing levels of carboxyhemoglobin in conscious dogs. The results demonstrate a linear increase in coronary flow and heart rate as the carboxyhemoglobin increases up to 20%. Myocardial oxygen consumption declined during the same period.

  13. The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction

    PubMed Central

    Dobaczewski, Marcin; Gonzalez-Quesada, Carlos; Frangogiannis, Nikolaos G

    2009-01-01

    The dynamic alterations in the cardiac extracellular matrix following myocardial infarction not only determine the mechanical properties of the infarcted heart, but also directly modulate the inflammatory and reparative response. During the inflammatory phase of healing, rapid activation of matrix metalloproteinases (MMP) causes degradation of the cardiac extracellular matrix. Matrix fragments exert potent pro-inflammatory actions, while MMPs process cytokines and chemokines altering their biological activity. In addition, vascular hyperpermeability results in extravasation of fibronectin and fibrinogen leading to formation of a plasma-derived provisional matrix that serves as a scaffold for leukocyte infiltration. Clearance of the infarct from dead cells and matrix debris is essential for resolution of inflammation and marks the transition to the proliferative phase. The fibrin-based provisional matrix is lysed and cellular fibronectin is secreted. ED-A fibronectin, mechanical tension and Transforming Growth Factor (TGF)-β are essential for modulation of fibroblasts into myofibroblasts, the main collagen-secreting cells in the wound. The matricellular proteins thrombospondin-1 and -2, osteopontin, tenascin-C, periostin, and secreted protein acidic and rich in cysteine (SPARC) are induced in the infarct regulating cellular interactions and promoting matrix organization. As the infarct matures, matrix cross-linking results in formation of a dense collagen-based scar. At this stage, shielding of fibroblasts from external mechanical tension by the mature matrix network may promote deactivation and cellular quiescence. The components of the extracellular matrix do not passively follow the pathologic alterations of the infarcted heart but critically modulate inflammatory and reparative pathways by transducing signals that affect cell survival, phenotype and gene expression. PMID:19631653

  14. Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.

    PubMed

    Ilkun, Olesya; Wilde, Nicole; Tuinei, Joseph; Pires, Karla M P; Zhu, Yi; Bugger, Heiko; Soto, Jamie; Wayment, Benjamin; Olsen, Curtis; Litwin, Sheldon E; Abel, E Dale

    2015-08-01

    Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism. PMID:26004364

  15. Streptomyces rhizobacteria modulate the secondary metabolism of Eucalyptus plants.

    PubMed

    Salla, Tamiris Daros; da Silva, Ramos; Astarita, Leandro Vieira; Santarém, Eliane Romanato

    2014-12-01

    The genus Eucalyptus comprises economically important species, such as Eucalyptus grandis and Eucalyptus globulus, used especially as a raw material in many industrial sectors. Species of Eucalyptus are very susceptible to pathogens, mainly fungi, which leads to mortality of plant cuttings in rooting phase. One alternative to promote plant health and development is the potential use of microorganisms that act as agents for biological control, such as plant growth-promoting rhizobacteria (PGPR). Rhizobacteria Streptomyces spp have been considered as PGPR. This study aimed at selecting strains of Streptomyces with ability to promote plant growth and modulate secondary metabolism of E. grandis and E. globulus in vitro plants. The experiments assessed the development of plants (root number and length), changes in key enzymes in plant defense (polyphenol oxidase and peroxidase) and induction of secondary compounds(total phenolic and quercetinic flavonoid fraction). The isolate Streptomyces PM9 showed highest production of indol-3-acetic acid and the best potential for root induction. Treatment of Eucalyptus roots with Streptomyces PM9 caused alterations in enzymes activities during the period of co-cultivation (1-15 days), as well as in the levels of phenolic compounds and flavonoids. Shoots also showed alteration in the secondary metabolism, suggesting induced systemic response. The ability of Streptomyces sp. PM9 on promoting root growth, through production of IAA, and possible role on modulation of secondary metabolism of Eucalyptus plants characterizes this isolate as PGPR and indicates its potential use as a biological control in forestry. PMID:25394796

  16. An intact small animal model of myocardial ischemia-reperfusion: Characterization of metabolic changes by hyperpolarized 13C MR spectroscopy.

    PubMed

    Yoshihara, Hikari A I; Bastiaansen, Jessica A M; Berthonneche, Corinne; Comment, Arnaud; Schwitter, Juerg

    2015-12-15

    Hyperpolarized carbon-13 magnetic resonance spectroscopy ((13)C MRS) enables the sensitive and noninvasive assessment of the metabolic changes occurring during myocardial ischemia-reperfusion. Ischemia-reperfusion models using hyperpolarized (13)C MRS are established in heart preparations ex vivo and in large animals in vivo, but an in vivo model in small animals would be advantageous to allow the study of reperfusion metabolism with neuroendocrine and inflammatory responses intact with the option to perform a greater number of experiments. A novel intact rat model of ischemia-reperfusion is presented that incorporates hyperpolarized (13)C MRS to characterize reperfusion metabolism. Typically, in an in vivo model, a tissue input function (TIF) is required to account for apparent changes in the metabolism of injected hyperpolarized [1-(13)C]pyruvate resulting from changes in perfusion. Whereas the measurement of a TIF by metabolic imaging is particularly challenging in small animals, the ratios of downstream metabolites can be used as an alternative. The ratio of [(13)C]bicarbonate:[1-(13)C]lactate (RatioBic/Lac) measured within 1-2 min after coronary release decreased vs. baseline in ischemic rats (n = 10, 15-min occlusion, controls: n = 10; P = 0.017 for interaction, 2-way ANOVA). The decrease in oxidative pyruvate metabolism [RatioBic/Lac(Ischemia)/RatioBic/Lac(Baseline)] modestly correlated with area at risk (r = 0.66; P = 0.002). Hyperpolarized (13)C MRS was also used to examine alanine production during ischemia, which is observed in ex vivo models, but no significant change was noted; metrics incorporating [1-(13)C]alanine did not substantially improve the discrimination of ischemic-reperfused myocardium from nonischemic myocardium. This intact rat model, which mimics the human situation of reperfused myocardial infarction, could be highly valuable for the testing of new drugs to treat reperfusion injury, thereby facilitating translational research. PMID

  17. Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

    PubMed

    Mather, K J; Hutchins, G D; Perry, K; Territo, W; Chisholm, R; Acton, A; Glick-Wilson, B; Considine, R V; Moberly, S; DeGrado, T R

    2016-03-15

    Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM. PMID:26732686

  18. Carotid baroreceptor stimulation prevents arrhythmias induced by acute myocardial infarction through autonomic modulation.

    PubMed

    Liao, Kai; Yu, Lilei; He, Bo; Huang, Bing; Yang, Kang; Saren, Gaowa; Wang, Songyun; Zhou, Xiaoya; Jiang, Hong

    2014-11-01

    : Electrical carotid baroreceptor stimulation (CBS) has shown therapeutic potential for resistant hypertension and heart failure by resetting autonomic nervous system, but the impacts on arrhythmias remains unclear. This study evaluated the effects of CBS on ventricular electrophysiological properties in normal dog heart and arrhythmias after acute myocardial infarction (AMI). In the acute protocol, anesthetized open chest dogs were exposed to 1 hour left anterior descending coronary occlusion as AMI model. Dogs were received either sham treatment (Control group, n = 8) or CBS (CBS group, n = 8), started 1 hour before AMI. CBS resulted in pronounced prolongation of ventricular effective refractory period and reduction of the maximum action potential duration restitution slope (from 0.85 ± 0.15 in the baseline state to 0.67 ± 0.09 at the end of 1 hour, P < 0.05) before AMI. Number of premature ventricular contractions (277 ± 168 in the Control group vs. 103 ± 84 in the CBS group, P < 0.05) and episodes of ventricular tachycardia/ventricular fibrillation (7 ± 3 in the Control group vs. 3 ± 2 in the CBS group, P < 0.05) was decreased compared with the control group during AMI. CBS buffered low-frequency/high-frequency ratio raise during AMI. Ischemic size was not affected by CBS. CBS may have a beneficial impact on ventricular arrhythmias induced by AMI through modulation of autonomic tone. PMID:24979392

  19. Influence of glyceryl trinitrate and nifedipine on coronary sinus blood flow and global myocardial metabolism during coronary artery operation.

    PubMed

    van Wezel, H B; Bovill, J G; Koolen, J J; Patrick, M R; Fiolet, J W; van der Stroom, J G

    1986-09-01

    The effects of intravenous infusions of glyceryl trinitrate and nifedipine on systemic haemodynamic function, coronary haemodynamic function, and global myocardial metabolism were compared in two groups of eleven patients with unimpaired left ventricular function undergoing elective coronary artery operation who were anaesthetised with high dose fentanyl. Severe post-sternotomy hypertension developed in three patients in the glyceryl trinitrate group who were resistant to the hypotensive effect of this agent. All patients given nifedipine remained haemodynamically stable. Coronary sinus blood flow and myocardial oxygen consumption increased and coronary vascular resistance decreased after sternotomy in the nifedipine group but not in the glyceryl trinitrate group. There is no satisfactory explanation for the apparently paradoxical increase in myocardial oxygen consumption in the patients given nifedipine. This phenomenon did not appear to be associated with any detrimental effect of left ventricular function. Thus nifedipine was better than glyceryl trinitrate for the control of post-sternotomy hypertension in patients with good left ventricular function. Intravenous nifedipine is not recommended, however, for the intraoperative control of blood pressure in patients with unstable angina or impaired left ventricular function. PMID:3092847

  20. Impact of the Metabolic Syndrome on the Clinical Outcome of Patients with Acute ST-Elevation Myocardial Infarction

    PubMed Central

    Lee, Min Goo; Ahn, Youngkeun; Chae, Shung Chull; Hur, Seung Ho; Hong, Taek Jong; Kim, Young Jo; Seong, In Whan; Chae, Jei Keon; Rhew, Jay Young; Chae, In Ho; Cho, Myeong Chan; Bae, Jang Ho; Rha, Seung Woon; Kim, Chong Jin; Choi, Donghoon; Jang, Yang Soo; Yoon, Junghan; Chung, Wook Sung; Cho, Jeong Gwan; Seung, Ki Bae; Park, Seung Jung

    2010-01-01

    We sought to determine the prevalence of metabolic syndrome (MS) in patients with acute myocardial infarction and its effect on clinical outcomes. Employing data from the Korea Acute Myocardial Infarction Registry, a total of 1,990 patients suffered from acute ST-elevation myocardial infarction (STEMI) between November 2005 and December 2006 were categorized according to the National Cholesterol Education Program-Adult Treatment Panel III criteria of MS. Primary study outcomes included major adverse cardiac events (MACE) during one-year follow-up. Patients were grouped based on existence of MS: group I: MS (n=1,182, 777 men, 62.8±12.3 yr); group II: Non-MS (n=808, 675 men, 64.2±13.1 yr). Group I showed lower left ventricular ejection fraction (LVEF) (P=0.005). There were no differences between two groups in the coronary angiographic findings except for multivessel involvement (P=0.01). The incidence of in-hospital death was higher in group I than in group II (P=0.047), but the rates of composite MACE during one-year clinical follow-up showed no significant differences. Multivariate analysis showed that low LVEF, old age, MS, low high density lipoprotein cholesterol and multivessel involvement were associated with high in-hospital death rate. In conclusion, MS is an important predictor for in-hospital death in patients with STEMI. PMID:20890426

  1. Association of genetic variants with myocardial infarction in Japanese individuals with or without metabolic syndrome

    PubMed Central

    KAWAMIYA, TOSHIKI; KATO, KIMIHIKO; HORIBE, HIDEKI; YOKOI, KIYOSHI; OGURI, MITSUTOSHI; YOSHIDA, TETSURO; FUJIMAKI, TETSUO; WATANABE, SACHIRO; SATOH, KEI; AOYAGI, YUKITOSHI; NOZAWA, YOSHINORI; MUROHARA, TOYOAKI; YAMADA, YOSHIJI

    2010-01-01

    The etiology of metabolic syndrome (MetS) is highly complex, with both genetic and environmental factors being thought to play an important role. Although MetS has been recognized as a risk factor for myocardial infarction (MI), the genetic risk for MI in individuals with or without MetS has remained uncharacterized. We examined a possible association of genetic variants with MI in individuals with or without MetS separately. The study population comprised 4,424 individuals, including 1,918 individuals with MetS (903 subjects with MI and 1,015 controls) and 2,506 individuals without MetS (499 subjects with MI and 2,007 controls). The 150 polymorphisms examined in the present study were selected by genome-wide association studies of MI and ischemic stroke with the use of Affymetrix GeneChip Human Mapping 500K Array Set. Initial screening by the Chi-square test revealed that the C→T polymorphism (rs1794429) of LRPAP1, the A→G polymorphism (rs12373237) of LAMA3 and the A→G polymorphism (rs3782257) of NCOR2 were significantly (false discovery rate of <0.05) associated with MI for individuals with MetS, and that the C→G polymorphism (rs13051704) of TFF1 was significantly related to MI for individuals without MetS. Subsequent multivariable logistic analysis with adjustment for covariates revealed that rs1794429 of LRPAP1 (recessive model; P=0.0218; odds ratio=0.71) and rs3782257 of NCOR2 (dominant model; P=0.0057; odds ratio=1.94) were significantly associated with MI among individuals with MetS, and that rs13051704 of TFF1 (additive model; P=0.0100; odds ratio=0.55) was significantly associated with MI among individuals without MetS. The genetic variants that confer susceptibility to MI differ between individuals with or without MetS. Stratification of subjects according to the presence or absence of MetS may thus be important for personalized prevention of MI based on genetic information. PMID:22993627

  2. Association of genetic variants with myocardial infarction in Japanese individuals with or without metabolic syndrome.

    PubMed

    Kawamiya, Toshiki; Kato, Kimihiko; Horibe, Hideki; Yokoi, Kiyoshi; Oguri, Mitsutoshi; Yoshida, Tetsuro; Fujimaki, Tetsuo; Watanabe, Sachiro; Satoh, Kei; Aoyagi, Yukitoshi; Nozawa, Yoshinori; Murohara, Toyoaki; Yamada, Yoshiji

    2010-11-01

    The etiology of metabolic syndrome (MetS) is highly complex, with both genetic and environmental factors being thought to play an important role. Although MetS has been recognized as a risk factor for myocardial infarction (MI), the genetic risk for MI in individuals with or without MetS has remained uncharacterized. We examined a possible association of genetic variants with MI in individuals with or without MetS separately. The study population comprised 4,424 individuals, including 1,918 individuals with MetS (903 subjects with MI and 1,015 controls) and 2,506 individuals without MetS (499 subjects with MI and 2,007 controls). The 150 polymorphisms examined in the present study were selected by genome-wide association studies of MI and ischemic stroke with the use of Affymetrix GeneChip Human Mapping 500K Array Set. Initial screening by the Chi-square test revealed that the C→T polymorphism (rs1794429) of LRPAP1, the A→G polymorphism (rs12373237) of LAMA3 and the A→G polymorphism (rs3782257) of NCOR2 were significantly (false discovery rate of <0.05) associated with MI for individuals with MetS, and that the C→G polymorphism (rs13051704) of TFF1 was significantly related to MI for individuals without MetS. Subsequent multivariable logistic analysis with adjustment for covariates revealed that rs1794429 of LRPAP1 (recessive model; P=0.0218; odds ratio=0.71) and rs3782257 of NCOR2 (dominant model; P=0.0057; odds ratio=1.94) were significantly associated with MI among individuals with MetS, and that rs13051704 of TFF1 (additive model; P=0.0100; odds ratio=0.55) was significantly associated with MI among individuals without MetS. The genetic variants that confer susceptibility to MI differ between individuals with or without MetS. Stratification of subjects according to the presence or absence of MetS may thus be important for personalized prevention of MI based on genetic information. PMID:22993627

  3. Proteomic and metabolomic changes driven by elevating myocardial creatine suggest novel metabolic feedback mechanisms.

    PubMed

    Zervou, Sevasti; Yin, Xiaoke; Nabeebaccus, Adam A; O'Brien, Brett A; Cross, Rebecca L; McAndrew, Debra J; Atkinson, R Andrew; Eykyn, Thomas R; Mayr, Manuel; Neubauer, Stefan; Lygate, Craig A

    2016-08-01

    Mice over-expressing the creatine transporter have elevated myocardial creatine levels [Cr] and are protected against ischaemia/reperfusion injury via improved energy reserve. However, mice with very high [Cr] develop cardiac hypertrophy and dysfunction. To investigate these contrasting effects, we applied a non-biased hypothesis-generating approach to quantify global protein and metabolite changes in the LV of mice stratified for [Cr] levels: wildtype, moderately elevated, and high [Cr] (65-85; 100-135; 160-250 nmol/mg protein, respectively). Male mice received an echocardiogram at 7 weeks of age with tissue harvested at 8 weeks. RV was used for [Cr] quantification by HPLC to select LV tissue for subsequent analysis. Two-dimensional difference in-gel electrophoresis identified differentially expressed proteins, which were manually picked and trypsin digested for nano-LC-MS/MS. Principal component analysis (PCA) showed efficient group separation (ANOVA P ≤ 0.05) and peptide sequences were identified by mouse database (UniProt 201203) using Mascot. A total of 27 unique proteins were found to be differentially expressed between normal and high [Cr], with proteins showing [Cr]-dependent differential expression, chosen for confirmation, e.g. α-crystallin B, a heat shock protein implicated in cardio-protection and myozenin-2, which could contribute to the hypertrophic phenotype. Nuclear magnetic resonance (¹H-NMR at 700 MHz) identified multiple strong correlations between [Cr] and key cardiac metabolites. For example, positive correlations with α-glucose (r² = 0.45; P = 0.002), acetyl-carnitine (r² = 0.50; P = 0.001), glutamine (r² = 0.59; P = 0.0002); and negative correlations with taurine (r² = 0.74; P < 0.0001), fumarate (r² = 0.45; P = 0.003), aspartate (r² = 0.59; P = 0.0002), alanine (r² = 0.66; P < 0.0001) and phosphocholine (r² = 0.60; P = 0.0002). These findings suggest wide-ranging and hitherto unexpected

  4. Patterned optogenetic modulation of neurovascular and metabolic signals

    PubMed Central

    Richner, Thomas J; Baumgartner, Ryan; Brodnick, Sarah K; Azimipour, Mehdi; Krugner-Higby, Lisa A; Eliceiri, Kevin W; Williams, Justin C; Pashaie, Ramin

    2015-01-01

    The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling. PMID:25388678

  5. Evaluation of myocardial metabolism, with /sup 13/N- and /sup 11/C-labeled amino acids and positron computed tomography

    SciTech Connect

    Henze, E.; Schelbert, H.R.; Barrio, J.R.; Egbert, J.E.; Hansen, H.W.; MacDonald, N.S.; Phelps, M.E.

    1982-08-01

    To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with /sup 13/N, and of /sup 11/C-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all /sup 13/N AA, and three (early, intermediate, late) for the two /sup 11/C compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for /sup 13/N-labeled Ala, Glu, Asp, and Leu, but not for /sup 13/N Gln and /sup 11/C compounds. Transaminase inhibition shortened the half-times of the late phases of /sup 13/N-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of /sup 13/N Gln and /sup 11/C Oxal; and resulted in a loss of /sup 11/C CO/sub 2/ production and of the intermediate phase for /sup 11/C Asp. On the PCT images, /sup 13/N activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by /sup 13/N NH/sub 3/ imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia.

  6. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization.

    PubMed

    Jha, Abhishek K; Huang, Stanley Ching-Cheng; Sergushichev, Alexey; Lampropoulou, Vicky; Ivanova, Yulia; Loginicheva, Ekaterina; Chmielewski, Karina; Stewart, Kelly M; Ashall, Juliet; Everts, Bart; Pearce, Edward J; Driggers, Edward M; Artyomov, Maxim N

    2015-03-17

    Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes. PMID:25786174

  7. Cardiac protection via metabolic modulation: an emerging role for incretin-based therapies?

    PubMed

    McCormick, Liam M; Kydd, Anna C; Dutka, David P

    2012-12-01

    Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre-clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease. PMID:22827290

  8. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion

    PubMed Central

    Lee, Hsin-Ling; Chen, Chwen-Lih; Yeh, Steve T.; Zweier, Jay L.

    2012-01-01

    Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R. Rat hearts were subjected to ischemia for 30 min followed by reperfusion for 1 h. Studies of mitochondrial function indicated a biphasic modulation of electron transfer activity (ETA) and ETC protein expression during I/R. Analysis of ETAs in the isolated mitochondria indicated that complexes I, II, III, and IV activities were diminished after 30 min of ischemia but increased upon restoration of flow. Immunoblotting analysis and ultrastructural analysis with transmission electron microscopy further revealed marked downregulation of ETC in the ischemic heart and then upregulation of ETC upon reperfusion. No significant difference in the mRNA expression level of ETC was detected between ischemic and postischemic hearts. However, reperfusion-induced ETC biosynthesis in myocardium can be inhibited by cycloheximide, indicating the involvement of translational control. Immunoblotting analysis of tissue homogenates revealed a similar profile in peroxisome proliferator-activated receptor-γ coactivator-1α expression, suggesting its essential role as an upstream regulator in controlling ETC biosynthesis during I/R. Significant impairment caused by ischemic and postischemic injury was observed in the complexes I- III. Analysis of NADH ferricyanide reductase activity indicated that injury of flavoprotein subcomplex accounts for 50% decline of intact complex I activity from ischemic heart. Taken together, our findings provide a new insight into the molecular mechanism of I/R-induced mitochondrial dysfunction. PMID:22268109

  9. Thoracic epidural anesthesia during coronary artery bypass surgery: effects on cardiac sympathetic activity, myocardial blood flow and metabolism, and central hemodynamics.

    PubMed

    Kirnö, K; Friberg, P; Grzegorczyk, A; Milocco, I; Ricksten, S E; Lundin, S

    1994-12-01

    The effects of high thoracic epidural anesthesia (TEA) on cardiac sympathetic nerve activity, myocardial blood flow and metabolism, and central hemodynamics were studied in 20 patients undergoing coronary artery bypass grafting (CABG). In 10 of the patients, TEA (T1-5 block) was used as an adjunct to a standardized fentanyl-nitrous oxide anesthesia. Hemodynamic measurements and blood sampling were performed after induction of anesthesia but prior to skin incision and after sternotomy. Assessment of total and cardiac sympathetic activity was performed by means of the norepinephrine kinetic approach. Prior to surgery, mean arterial pressure (MAP), great cardiac vein flow (GCVF), and regional myocardial oxygen consumption (Reg-MVO2) were lower in the TEA group compared to the control group. During sternotomy there was a pronounced increase in cardiac norepinephrine spillover, MAP, systemic vascular resistance index (SVRI), pulmonary capillary wedge pressure (PCWP), GCVF, and Reg-MVO2 in the control group. These changes were clearly attenuated in the TEA group. None of the patients in the TEA group had metabolic (lactate) or electrocardiographic signs of myocardial ischemia. Three patients in the control group had indices of myocardial ischemia prior to and/or during surgery. We conclude that TEA attenuates the surgically mediated sympathetic stress response to sternotomy, thereby preventing the increase in myocardial oxygen demand in the pre-bypass period without jeopardizing myocardial perfusion. PMID:7978429

  10. Legionella pneumophila restrains autophagy by modulating the host's sphingolipid metabolism.

    PubMed

    Rolando, Monica; Escoll, Pedro; Buchrieser, Carmen

    2016-06-01

    Sphingolipids are bioactive molecules playing a key role as membrane components, but they are also central regulators of many intracellular processes including macroautophagy/autophagy. In particular, sphingosine-1-phosphate (S1P) is a critical mediator that controls the balance between sphingolipid-induced autophagy and cell death. S1P levels are adjusted via S1P synthesis, dephosphorylation or degradation, catalyzed by SGPL1 (sphingosine-1-phosphate lyase 1). Intracellular pathogens are able to modulate many different host cell pathways to allow their replication. We have found that infection of eukaryotic cells with the human pathogen Legionella pneumophila triggers a change in the host cell sphingolipid metabolism and specifically affects the levels of sphingosine. Indeed, L. pneumophila secretes a protein highly homologous to eukaryotic SGPL1 (named LpSPL). We solved the crystal structure of LpSPL and showed that it encodes lyase activity, targets the host's sphingolipid metabolism, and plays a role in starvation-induced autophagy during L. pneumophila infection to promote intracellular survival. PMID:27191778

  11. Modulation of metabolic syndrome-related inflammation by cocoa.

    PubMed

    Gu, Yeyi; Lambert, Joshua D

    2013-06-01

    Cocoa (Theobroma cacao L., Sterculiaceae) is a widely consumed food ingredient. Although typically found in high-fat, high-sugar foods such as chocolate, cocoa is rich in polyphenols, methylxanthines, and monounsaturated fatty acids. There is increasing evidence that moderate consumption of cocoa and cocoa-containing foods may have beneficial effects on the health including vasodilatory, antioxidant, and anti-inflammatory effects. Polyphenols in cocoa, including monomeric flavanols, as well as polymeric proanthocyanidins, may play a role in these observed beneficial effects. Chronic inflammation represents a potential mechanistic link between obesity and its related pathologies: insulin resistance, dyslipidemia, and hypertension, which comprise the metabolic syndrome. In the present review, we discuss the available data regarding the modulation of metabolic syndrome-related inflammation by cocoa and cocoa-derived compounds. We emphasize studies using laboratory animals or human subjects since such studies often represent the strongest available evidence for biological effects. In vitro studies are included to provide some mechanistic context, but are critically interpreted. Although the available data seem to support the anti-inflammatory effects of cocoa, further studies are needed with regard to the dose-response relationship as well as the underlying mechanisms of action. We hope this review will stimulate further research on cocoa and its anti-inflammatory activities. PMID:23637048

  12. Bacterial microcompartments as metabolic modules for plant synthetic biology.

    PubMed

    Gonzalez-Esquer, C Raul; Newnham, Sarah E; Kerfeld, Cheryl A

    2016-07-01

    Bacterial microcompartments (BMCs) are megadalton-sized protein assemblies that enclose segments of metabolic pathways within cells. They increase the catalytic efficiency of the encapsulated enzymes while sequestering volatile or toxic intermediates from the bulk cytosol. The first BMCs discovered were the carboxysomes of cyanobacteria. Carboxysomes compartmentalize the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) with carbonic anhydrase. They enhance the carboxylase activity of RuBisCO by increasing the local concentration of CO2 in the vicinity of the enzyme's active site. As a metabolic module for carbon fixation, carboxysomes could be transferred to eukaryotic organisms (e.g. plants) to increase photosynthetic efficiency. Within the scope of synthetic biology, carboxysomes and other BMCs hold even greater potential when considered a source of building blocks for the development of nanoreactors or three-dimensional scaffolds to increase the efficiency of either native or heterologously expressed enzymes. The carboxysome serves as an ideal model system for testing approaches to engineering BMCs because their expression in cyanobacteria provides a sensitive screen for form (appearance of polyhedral bodies) and function (ability to grow on air). We recount recent progress in the re-engineering of the carboxysome shell and core to offer a conceptual framework for the development of BMC-based architectures for applications in plant synthetic biology. PMID:26991644

  13. Inflammation, oxidative stress and metabolic syndrome: dietary modulation.

    PubMed

    Fernández-García, José C; Cardona, Fernando; Tinahones, Francisco J

    2013-11-01

    The metabolic syndrome (MetS) is a cluster of risk factors for the development of cardiovascular disease and type 2 diabetes mellitus. These risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. MetS has become a serious public health and clinical problem whose prevalence and incidence are increasing along with the worldwide rise in rates of obesity and sedentary lifestyles. A number of studies have shown that MetS is associated with a state of low-grade inflammation, characterized by abnormal pro-inflammatory cytokine production, increased acute-phase reactants, and activation of a network of inflammatory signalling pathways. Moreover, MetS has also been linked to oxidative stress, a consequence of a reduction in the antioxidant systems and an increase in the production of reactive oxygen species. Nevertheless, agreement exists that dietary intervention may modulate the pro-inflammatory state and lessen oxidative stress related to MetS, thereby decreasing the cardiovascular risk. In this review we address the current available evidence regarding dietary modulation of inflammation and oxidative stress associated with MetS. PMID:24168441

  14. Wnt11 Gene Therapy with Adeno-associated Virus 9 Improves Recovery from Myocardial Infarction by Modulating the Inflammatory Response

    PubMed Central

    Morishita, Yoshihiro; Kobayashi, Koichi; Klyachko, Ekaterina; Jujo, Kentaro; Maeda, Kengo; Losordo, Douglas W.; Murohara, Toyoaki

    2016-01-01

    Acute myocardial infarction induces activation of the acute phase response and infiltration of leukocytes to the infarcted area. Moreover, myocardium that is remote from ischemic area also becomes inflamed. Inflammatory reaction clears dead cells and matrix debris, while prolongation or expansion of the inflammatory response results in dysfunction following myocardial infarction. Wnt glycolipoproteins are best characterized as regulators of embryonic development. Recently several reports suggest that they also contribute to the inflammatory response in adult animals. However, the effects of Wnt proteins on myocardial infarction have not been explored. Here we show that Wnt11 expression leads to significant improvements of survival and cardiac function by suppressing infiltration of multiple kinds of inflammatory cells in infarcted heart. Wnt11 protein suppresses gene expression of inflammatory cytokines through the modulation of NF-κB in vitro. These results reveal a novel function of Wnt11 in the regulation of inflammatory response and provide a rationale for the use of Wnt11 to manipulate human diseases that are mediated by inflammation. PMID:26882996

  15. Effect of Shen-Fu Injection Pretreatment to Myocardial Metabolism During Untreated Ventricular Fibrillation in a Porcine Model

    PubMed Central

    Yuan, Wei; Wu, Jun-Yuan; Wang, Guo-Xing; Zhang, Qian; Li, Chun-Sheng

    2015-01-01

    Background: Shen-Fu injection (SFI) can attenuate ischemia-reperfusion injury, protect cardiac function, and improve microcirculation during cardiopulmonary resuscitation. We hypothesized that SFI may also have an influence on myocardial metabolism during ventricular fibrillation (VF). In this study, we used SFI pretreatment prior to VF to discuss the changes of myocardial metabolism and catecholamine (CA) levels during untreated VF, trying to provide new evidence to the protection of SFI to myocardium. Methods: Twenty-four pigs were divided into three groups: Saline group (SA group), SFI group, and SHAM operation group (SHAM group). Thirty minutes prior to the induction of VF, the SFI group received 0.24 mg/ml SFI through an intravenous injection; the SA group received an equal amount of sodium chloride solution. The interstitial fluid from the left ventricle (LV) wall was collected through the microdialysis tubes during VF. Adenosine diphosphate (ADP), adenosine triphosphate (ATP), and Na+ -K+ -ATPase and Ca2+ -ATPase enzyme activities were measured after untreated VF. Peak-to-trough VF amplitude and median frequency were analyzed for each of these 5-s intervals. Results: The levels of glucose and glutamate were lower after VF in both the SA and SFI groups, compared with baseline, and the levels in the SFI group were higher than those in the SA group. Compared with baseline, the levels of lactate and the lactate/pyruvate ratio increased after VF in both SA and SFI groups, and the levels in the SFI group were lower than those in the SA group. In both the SA and SFI groups, the levels of dopamine, norepinephrine, and epinephrine increased significantly. There were no statistical differences between the two groups. The content of ATP, ADP, and phosphocreatine in the SFI group was higher than those in the SA group. The activity of LV Na+ -K+ -ATPase was significantly higher in the SFI group than in the SA group. Amplitude mean spectrum area (AMSA) was significantly

  16. Differential effects of octanoate and heptanoate on myocardial metabolism during extracorporeal membrane oxygenation in an infant swine model.

    PubMed

    Kajimoto, Masaki; Ledee, Dolena R; Olson, Aaron K; Isern, Nancy G; Des Rosiers, Christine; Portman, Michael A

    2015-10-01

    Nutritional energy support during extracorporeal membrane oxygenation (ECMO) should promote successful myocardial adaptation and eventual weaning from the ECMO circuit. Fatty acids (FAs) are a major myocardial energy source, and medium-chain FAs (MCFAs) are easily taken up by cell and mitochondria without membrane transporters. Odd-numbered MCFAs supply carbons to the citric acid cycle (CAC) via anaplerotic propionyl-CoA as well as acetyl-CoA, the predominant β-oxidation product for even-numbered MCFA. Theoretically, this anaplerotic pathway enhances carbon entry into the CAC, and provides superior energy state and preservation of protein synthesis. We tested this hypothesis in an immature swine model undergoing ECMO. Fifteen male Yorkshire pigs (26-45 days old) with 8-h ECMO received either normal saline, heptanoate (odd-numbered MCFA), or octanoate (even-numbered MCFA) at 2.3 μmol·kg body wt(-1)·min(-1) as MCFAs systemically during ECMO (n = 5/group). The 13-carbon ((13)C)-labeled substrates ([2-(13)C]lactate, [5,6,7-(13)C3]heptanoate, and [U-(13)C6]leucine) were systemically infused as metabolic markers for the final 60 min before left ventricular tissue extraction. Extracted tissues were analyzed for the (13)C-labeled and absolute concentrations of metabolites by nuclear magnetic resonance and gas chromatography-mass spectrometry. Octanoate produced markedly higher myocardial citrate concentration, and led to a higher [ATP]-to-[ADP] ratio compared with other groups. Unexpectedly, octanoate and heptanoate increased the flux of propionyl-CoA relative to acetyl-CoA into the CAC compared with control. MCFAs promoted increases in leucine oxidation, but were not associated with a difference in protein synthesis rate. In conclusion, octanoate provides energetic advantages to the heart over heptanoate. PMID:26232235

  17. Differential Effects Of Octanoate And Heptanoate On Myocardial Metabolism During Extracorporeal Membrane Oxygenation In An Infant Swine Model

    SciTech Connect

    Kajimoto, Masaki; Ledee, Dolena R.; Isern, Nancy G.; Olson, Aaron; Des Rosiers, Christine; Portman, Michael A.

    2015-10-01

    Background: Nutritional energy support during extracorporeal membrane oxygenation (ECMO) should promote successful myocardial adaptation and eventual weaning from the ECMO circuit. Fatty acids (FAs) are a major myocardial energy source, and medium-chain FAs (MCFAs) are easily taken up by cell and mitochondria without membrane transporters. Oddnumbered MCFAs supply carbons to the citric acid cycle (CAC) via anaplerotic propionyl-CoA as well as acetyl-CoA, the predominant betaoxidation product for even-numbered MCFA. Theoretically, this anaplerotic pathway enhances carbon entry into the CAC, and provides superior energy state and preservation of protein synthesis. We tested this hypothesis in an immature swine model undergoing ECMO. Methods: Fifteen male Yorkshire pigs (26-45 days old) with 8-hour ECMO were received either normal saline, heptanoate (odd-numbered MCFA) or octanoate (even-numbered MCFA) at 2.3 μmol/kg body wt/min as MCFAs systemically during ECMO (n = 5 per group). The 13-Carbon (13C)-labeled substrates ([2-13C]lactate, [5,6,7-13C3]heptanoate and [U-13C6]leucine) were systemically infused as metabolic markers for the final 60 minutes before left ventricular tissue extraction. Extracted tissues were analyzed for the 13C-labeled and absolute concentrations of metabolites by nuclear magnetic resonance and gas chromatography-mass spectrometry. Results: Octanoate produced markedly higher myocardial citrate concentration, and led to a higher [ATP]/[ADP] ratio compared with other http://mc.manuscriptcentral.com/jpen Journal of Parenteral and Enteral Nutrition For Peer Review groups. Unexpectedly, octanoate increased the flux of propionyl-CoA relative to acetyl-CoA into the CAC as well as heptanoate. MCFAs promoted increases in leucine oxidation, but were not associated with a difference in fractional protein synthesis rate. Conclusion: Octanoate provides energetic advantages to the heart over heptanoate, while preserving protein synthesis.

  18. Reduction of isoproterenol-induced cardiac hypertrophy and modulation of myocardial connexin43 by a KATP channel agonist.

    PubMed

    Sun, Ji-Min; Wang, Chun-Miao; Guo, Zeng; Hao, Yu-Yu; Xie, Yang-Jing; Gu, Jian; Wang, Ai-Ling

    2015-03-01

    Cardiac hypertrophy is a compensatory mechanism that occurs in conjunction with cardiovascular diseases. Although hypertrophy of the myocardium provides certain benefits during the early stages of cardiovascular disease, prolonged hypertrophy is potentially harmful to the heart and can result in arrhythmia and heart failure. The aim of this study was to investigate whether an ATP‑sensitive K+ (KATP) channel agonist was capable of reducing isoproterenol (Iso)‑induced cardiac hypertrophy and modulating myocardial connexin43 (Cx43) expression. Fifty male Sprague Dawley rats were randomly assigned to five groups: Normal, vehicle, nicorandil, glibenclamide and nicorandil plus glibenclamide. Rats in the four treatment groups received Iso injection for seven days, followed by administration with saline, nicorandil, glibenclamide or a combination of nicorandil and glibenclamide, respectively, for four weeks. Cardiac hypertrophy was then evaluated by measuring body weight, heart weight and left‑ventricular weight, and plasma B‑type natriuretic peptide levels were evaluated by ELISA. Immunocytochemistry and a reverse transcription‑polymerase chain reaction were performed to detect the spatial distribution and gene expression of myocardial Cx43, respectively. The KATP channel agonist nicorandil markedly attenuated the degree of myocardial hypertrophy induced by Iso as compared with the vehicle group. Myocardial Cx43 expression was significantly decreased and redistributed following cardiac hypertrophy. The decrease and redistribution of Cx43 was reduced following treatment with the KATP channel agonist nicorandil. Addition of the KATP channel blocker glibenclamide eliminated the beneficial effects of nicorandil against hypertrophy and on connexin43. In conclusion, the present study indicated that chronic use of KATP channel agonists following cardiac hypertrophy can attenuate ventricular remodeling and upregulate the expression level and spatial distribution of Cx43

  19. Temporal changes in phosphatidylserine expression and glucose metabolism after myocardial infarction: an in vivo imaging study in mice.

    PubMed

    Lehner, Sebastian; Todica, Andrei; Brunner, Stefan; Uebleis, Christopher; Wang, Hao; Wängler, Carmen; Herbach, Nadja; Herrler, Tanja; Böning, Guido; Laubender, Rüdiger Paul; Cumming, Paul; Schirrmacher, Ralf; Franz, Wolfgang; Hacker, Marcus

    2012-01-01

    Positron emission tomography (PET) for in vivo monitoring of phosphatidylserine externalization and glucose metabolism can potentially provide early predictors of outcome of cardioprotective therapies after myocardial infarction. We performed serial [⁶⁸Ga]annexin A5 PET (annexin-PET) and [¹⁸F]fluorodeoxyglucose PET (FDG-PET) after myocardial infarction to determine the time of peak phosphatidylserine externalization in relation to impaired glucose metabolism in infracted tissue. Annexin- and FDG-PET recordings were obtained in female (C57BL6/N) mice on days 1 to 4 after ligation of the left anterior descending (LAD) artery. [⁶⁸Ga]annexin A5 uptake (%ID/g) in the LAD artery territory increased from 1.7 ± 1.1 on day 1 to 5.0 ± 3.3 on day 2 and then declined to 2.0 ± 1.4 on day 3 (p  =  .047 vs day 2) and 1.6 ± 1.4 on day 4 (p  =  .014 vs day 2). These results matched apoptosis rates as estimated by autoradiography and fluorescein staining. FDG uptake (%ID/g) declined from 28 ± 14 on day 1 to 14 ± 3.5 on day 4 (p < .0001 vs day 1). Whereas FDG-PET revealed continuous loss of cell viability after permanent LAD artery occlusion, annexin-PET indicated peak phosphatidylserine expression at day 2, which might be the optimal time point for therapy monitoring. PMID:23084247

  20. Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus

    PubMed Central

    Babst, Benjamin A.; Chen, Han-Yi; Wang, Hong-Qiang; Payyavula, Raja S.; Thomas, Tina P.; Harding, Scott A.; Tsai, Chung-Jui

    2014-01-01

    The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1-316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated UGT84A17. Recombinant protein analysis showed that UGT84A17 is a hydroxycinnamate glycosyltransferase and able to accept a range of unsubstituted and substituted cinnamic and benzoic acids as substrates in vitro. Overexpression of GT1-316 in transgenic Populus led to plant-wide increases of hydroxycinnamoyl-glucose esters, which were further elevated under N-limiting conditions. Levels of the two most abundant flavonoid glycosides, rutin and kaempferol-3-O-rutinoside, decreased, while levels of other less abundant flavonoid and phenylpropanoid conjugates increased in leaves of the GT1-316-overexpressing plants. Transcript levels of representative phenylpropanoid pathway genes were unchanged in transgenic plants, supporting a glycosylation-mediated redirection of phenylpropanoid carbon flow as opposed to enhanced phenylpropanoid pathway flux. The metabolic response of N-replete transgenic plants overlapped with that of N-stressed wild types, as the majority of phenylpropanoid derivatives significantly affected by GT1-316 overexpression were also significantly changed by N stress in the wild types. These results suggest that UGT84A17 plays an important role in phenylpropanoid metabolism by modulating biosynthesis of hydroxycinnamoyl-glucose esters and their derivatives in response to developmental and environmental cues. PMID:24803501

  1. Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the dir...

  2. Positron emission reconstruction tomography for the assessment of regional myocardial metabolism by the administration of substrates labeled with cyclotron produced radionuclides

    NASA Technical Reports Server (NTRS)

    Ter-Pogossian, M. M.; Hoffman, E. J.; Weiss, E. S.; Coleman, R. E.; Phelps, M. E.; Welch, M. J.; Sobel, B. E.

    1975-01-01

    A positron emission transverse tomograph device was developed which provides transaxial sectional images of the distribution of positron-emitting radionuclides in the heart. The images provide a quantitative three-dimensional map of the distribution of activity unencumbered by the superimposition of activity originating from regions overlying and underlying the plane of interest. PETT is used primarily with the cyclotron-produced radionuclides oxygen-15, nitrogen-13 and carbon-11. Because of the participation of these atoms in metabolism, they can be used to label metabolic substrates and intermediary molecules incorporated in myocardial metabolism.

  3. Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota?

    PubMed

    Brahe, Lena K; Astrup, Arne; Larsen, Lesli H

    2016-01-01

    Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment. PMID:26773017

  4. Myocardial Po2 does not limit aerobic metabolism in the postischemic heart.

    PubMed

    Chung, Youngran

    2016-01-15

    Reperfused hypertrophic hearts are prone to develop reflow abnormalities, which are likely to impair O2 return to the myocardium. Yet, reflow deficit may not be the only factor determining postischemic oxygenation in the hypertrophic heart. Altered O2 demand may also contribute to hypoxia. In addition, the extent to which myocardial Po2 dictates energy and functional recovery in the reperfused heart remains uncertain. In the present study, moderately hypertrophied hearts from spontaneously hypertensive rats were subjected to ischemia-reperfusion, and the recovery time courses of pH and high-energy phosphates were followed by (31)P NMR. (1)H NMR measurement of intracellular myoglobin assessed tissue O2 levels. The present study found that the exacerbation of hypoxia in the postischemic spontaneously hypertensive rat heart arises mostly from impaired microvascular supply of O2. However, postischemic myocardial Po2, at least when it exceeds ∼18% of the preischemic level, does not limit mitochondrial respiration and high-energy phosphate resynthesis. It only passively reflects changes in the O2 supply-demand balance. PMID:26589325

  5. Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris

    PubMed Central

    Rousseau, M. F.; Vincent, M. F.; Cheron, P.; Van Den Berghe, G.; Charlier, A. A.; Pouleur, H.

    1985-01-01

    1 The effects of intravenous nicardipine (2.5 mg) on the left ventricular (LV) inotropic state, LV metabolism, and coronary haemodynamics were analysed in 22 patients with angina pectoris. 2 Measurements were made at fixed heart rate (atrial pacing), under basal state, and during a cold pressor test. 3 After nicardipine, coronary blood flow and oxygen content in the coronary sinus increased significantly. 4 The indices of inotropic state increased slightly, and the rate of isovolumic LV pressure fall improved. 5 Myocardial oxygen consumption was unchanged despite the significant reduction in pressure-rate product, but LV lactate uptake increased, particularly during the cold pressor test. 6 When nicardipine was administered after propranolol, the indices of inotropic state were unaffected. 7 The lack of direct effect of nicardipine on LV inotropic state was further confirmed by intracoronary injection of 0.1 and 0.2 mg in a separate group of 10 patients. 8 It is concluded that the nicardipine-induced coronary dilatation seems to improve perfusion and aerobic metabolism in areas with chronic ischaemia, resulting in reduced lactate production and augmented oxygen consumption. PMID:2862900

  6. Hydrogen sulfide modulates sub-cellular susceptibility to oxidative stress induced by myocardial ischemic reperfusion injury.

    PubMed

    Ansari, Shakila Banu; Kurian, Gino A

    2016-05-25

    In this study, we compared the impact of H2S pre (HIPC) and post-conditioning (HPOC) on oxidative stress, the prime reason for myocardial ischemia reperfusion injury (I/R), in different compartments of the myocardium, such as the mitochondria beside its subpopulations (interfibrillar (IFM) and subsarcolemmal (SSM) mitochondria) and microsomal fractions in I/R injured rat heart. The results demonstrated that compared to I/R rat heart, HIPC and HPOC treated hearts shows reduced myocardial injury, enhanced antioxidant enzyme activities and reduced the level of TBARS in different cellular compartments. The extent of recovery (measured by TBARS and GSH levels) in subcellular fractions, were in the following descending order: microsome > SSM > IFM in both HIPC and HPOC. In summary, oxidative stress mediated mitochondrial dysfunction, one of the primary causes for I/R injury, was partly recovered by HIPC and HPOC treatment, with significant improvement in SSM fraction compared to the IFM. PMID:27041072

  7. Modulators of Hepatic Lipoprotein Metabolism Identified in a Search for Small-Molecule Inducers of Tribbles Pseudokinase 1 Expression

    PubMed Central

    Nagiec, Marek M.; Skepner, Adam P.; Negri, Joseph; Eichhorn, Michelle; Kuperwasser, Nicolas; Comer, Eamon; Muncipinto, Giovanni; Subramanian, Aravind; Clish, Clary; Musunuru, Kiran; Duvall, Jeremy R.; Foley, Michael; Perez, Jose R.; Palmer, Michelle A. J.

    2015-01-01

    Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces secretion of VLDL and is associated with lower plasma levels of LDL cholesterol and triglycerides, higher plasma levels of HDL cholesterol and reduced risk for myocardial infarction, we carried out a high throughput phenotypic screen based on quantitative RT-PCR assay to identify compounds that induce TRIB1 expression in human HepG2 hepatoma cells. In a screen of a collection of diversity-oriented synthesis (DOS)-derived compounds, we identified a series of benzofuran-based compounds that upregulate TRIB1 expression and phenocopy the effects of TRIB1 cDNA overexpression, as they inhibit triglyceride synthesis and apoB secretion in cells. In addition, the compounds downregulate expression of MTTP and APOC3, key components of the lipoprotein assembly pathway. However, CRISPR-Cas9 induced chromosomal disruption of the TRIB1 locus in HepG2 cells, while confirming its regulatory role in lipoprotein metabolism, demonstrated that the effects of benzofurans persist in TRIB1-null cells indicating that TRIB1 is sufficient but not necessary to transmit the effects of the drug. Remarkably, active benzofurans, as well as natural products capable of TRIB1 upregulation, also modulate hepatic cell cholesterol metabolism by elevating the expression of LDLR transcript and LDL receptor protein, while reducing the levels of PCSK9 transcript and secreted PCSK9 protein and stimulating LDL uptake. The effects of benzofurans are not masked by cholesterol depletion and are independent of the SREBP-2 regulatory circuit, indicating that these compounds represent a novel class of chemically tractable small-molecule modulators that shift cellular lipoprotein metabolism in HepG2 cells from lipogenesis to scavenging. PMID:25811180

  8. Cardiac Per2 Functions as Novel Link between Fatty Acid Metabolism and Myocardial Inflammation during Ischemia and Reperfusion Injury of the Heart

    PubMed Central

    Bonney, Stephanie; Kominsky, Doug; Brodsky, Kelley; Eltzschig, Holger; Walker, Lori; Eckle, Tobias

    2013-01-01

    Disruption of peripheral circadian rhyme pathways dominantly leads to metabolic disorders. Studies on circadian rhythm proteins in the heart indicated a role for Clock or Per2 in cardiac metabolism. In contrast to Clock−/−, Per2−/− mice have larger infarct sizes with deficient lactate production during myocardial ischemia. To test the hypothesis that cardiac Per2 represents an important regulator of cardiac metabolism during myocardial ischemia, we measured lactate during reperfusion in Per1−/−, Per2−/− or wildtype mice. As lactate measurements in whole blood indicated an exclusive role of Per2 in controlling lactate production during myocardial ischemia, we next performed gene array studies using various ischemia-reperfusion protocols comparing wildtype and Per2−/− mice. Surprisingly, high-throughput gene array analysis revealed dominantly lipid metabolism as the differentially regulated pathway in wildtype mice when compared to Per2−/−. In all ischemia-reperfusion protocols used, the enzyme enoyl-CoA hydratase, which is essential in fatty acid beta-oxidation, was regulated in wildtype animals only. Studies using nuclear magnet resonance imaging (NMRI) confirmed altered fatty acid populations with higher mono-unsaturated fatty acid levels in hearts from Per2−/− mice. Unexpectedly, studies on gene regulation during reperfusion revealed solely pro inflammatory genes as differentially regulated ‘Per2-genes’. Subsequent studies on inflammatory markers showed increasing IL-6 or TNFα levels during reperfusion in Per2−/− mice. In summary, these studies reveal an important role of cardiac Per2 for fatty acid metabolism and inflammation during myocardial ischemia and reperfusion, respectively. PMID:23977055

  9. Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders.

    PubMed

    Barandas, Rita; Landgraf, Dominic; McCarthy, Michael J; Welsh, David K

    2015-12-01

    Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms. PMID:26483181

  10. Total Mechanical Unloading Minimizes Metabolic Demand of Left Ventricle and Dramatically Reduces Infarct Size in Myocardial Infarction

    PubMed Central

    Kakino, Takamori; Arimura, Takahiro; Sakamoto, Takafumi; Nishikawa, Takuya; Sakamoto, Kazuo; Ikeda, Masataka; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

    2016-01-01

    Background Left ventricular assist device (LVAD) mechanically unloads the left ventricle (LV). Theoretical analysis indicates that partial LVAD support (p-LVAD), where LV remains ejecting, reduces LV preload while increases afterload resulting from the elevation of total cardiac output and mean aortic pressure, and consequently does not markedly decrease myocardial oxygen consumption (MVO2). In contrast, total LVAD support (t-LVAD), where LV no longer ejects, markedly decreases LV preload volume and afterload pressure, thereby strikingly reduces MVO2. Since an imbalance in oxygen supply and demand is the fundamental pathophysiology of myocardial infarction (MI), we hypothesized that t-LVAD minimizes MVO2 and reduces infarct size in MI. The purpose of this study was to evaluate the differential impact of the support level of LVAD on MVO2 and infarct size in a canine model of ischemia-reperfusion. Methods In 5 normal mongrel dogs, we examined the impact of LVAD on MVO2 at 3 support levels: Control (no LVAD support), p-LVAD and t-LVAD. In another 16 dogs, ischemia was induced by occluding major branches of the left anterior descending coronary artery (90 min) followed by reperfusion (300 min). We activated LVAD from the beginning of ischemia until 300 min of reperfusion, and compared the infarct size among 3 different levels of LVAD support. Results t-LVAD markedly reduced MVO2 (% reduction against Control: -56 ± 9%, p<0.01) whereas p-LVAD did less (-21 ± 14%, p<0.05). t-LVAD markedly reduced infarct size compared to p-LVAD (infarct area/area at risk: Control; 41.8 ± 6.4, p-LVAD; 29.1 ± 5.6 and t-LVAD; 5.0 ± 3.1%, p<0.01). Changes in creatine kinase-MB paralleled those in infarct size. Conclusions Total LVAD support that minimizes metabolic demand maximizes the benefit of LVAD in the treatment of acute myocardial infarction. PMID:27124411

  11. Myocardial metabolism of fluorodeoxyglucose compared to cell membrane integrity for the potassium analogue rubidium-82 for assessing infarct size in man by PET

    SciTech Connect

    Gould, K.L.; Yoshida, K.; Hess, M.J.; Haynie, M.; Mullani, N.; Smalling, R.W. )

    1991-01-01

    Potassium loss from damaged myocardial cells is linearly related to CPK enzyme loss reflecting extent of necrosis. The potassium analog, rubidium-82 (82Rb), is extracted after i.v. injection and retained in viable myocardium but is not trapped or washed out of necrotic regions. To compare myocardial cell metabolism with membrane dysfunction as indicators of necrosis/viability, 43 patients with evolving myocardial infarction and coronary arteriography had positron emission tomography using fluorodeoxyglucose (FDG) and the potassium analog 82Rb. Percent of heart showing FDG defects and 82Rb washout on sequential images indicating failure to retain the potassium analogue were visually assessed and quantified by automated software. Infarct size based on rubidium kinetics correlated closely with size and location on FDG images (visual r = 0.93, automated r = 0.82), suggesting that loss of cell membrane integrity for trapping the potassium analog 82Rb parallels loss of intracellular glucose metabolism, both comparable quantitative markers of myocardial necrosis/viability.

  12. Myocardial metabolism, perfusion, wall motion and electrical activity in Duchenne muscular dystrophy

    SciTech Connect

    Perloff, J.K.; Henze, E.; Schelbert, H.R.

    1982-01-01

    The cardiomyopathy of Duchenne's muscular dystrophy originates in the posterobasal left ventricle and extends chiefly to the contiguous lateral wall. Ultrastructural abnormalities in these regions precede connective tissue replacement. We postulated that a metabolic fault coincided with or antedated the subcellular abnormality. Accordingly, regional left ventricular metabolism, perfusion and wall motion were studied using positron computed tomography and metabolic isotopes supplemented by thallium perfusion scans, equilibrium radionuclide angiography and M-mode and two-dimensional echocardiography. To complete the assessment, electrocardiograms, vectorcardiograms, 24 hour taped electrocardiograms and chest x-rays were analyzed. Positron computed tomography utilizing F-18 2-fluoro 2-deoxyglucose (FDG) provided the first conclusive evidence supporting the hypothesis of a premorphologic regional metabolic fault. Thus, cardiac involvement in duchenne dystrophy emerges as a unique form of heart disease, genetically targeting specific regions of ventricular myocardium for initial metabolic and subcellular changes. Reported ultrastructural abnormalities of the impulse and conduction systems provide, at least in part, a basis for the clinically observed sinus node, intraatrial, internodal, AV nodal and infranodal disorders.

  13. Myocardial mechanical dysfunction following endotoxemia: role of changes in energy substrate metabolism.

    PubMed

    Soraya, Hamid; Masoud, Waleed G T; Gandhi, Manoj; Garjani, Alireza; Clanachan, Alexander S

    2016-03-01

    Cardiovascular depression due to endotoxemia remains a major cause of mortality in intensive care patients. To determine whether drug-induced alterations in cardiac metabolism may be a viable strategy to reduce endotoxemia-mediated cardiac dysfunction, we assessed endotoxemia-induced changes in glucose and fatty acid metabolism under aerobic and post-ischemic conditions. Endotoxemia was induced in male Sprague-Dawley rats by lipopolysaccharide (Escherichia coli 0111:B4c, 4 mg/kg, i.p.) 6 h prior to heart removal for ex vivo assessment of left ventricular (LV) work and rates of glucose metabolism (glucose uptake, glycogen synthesis, glycolysis and glucose oxidation) and palmitate oxidation. Under aerobic conditions, endotoxemic hearts had impaired LV function as judged by echocardiography in vivo (% ejection fraction, 66.0 ± 3.2 vs 78.0 ± 2.1, p < 0.05) or by LV work ex vivo (2.14 ± 0.16 vs 3.28 ± 0.16, Joules min(-1) g dry wt(-1), p < 0.05). However, rates of glucose uptake, glycogen synthesis, glycolysis, and glucose oxidation were not altered. Palmitate oxidation was lower in endotoxemic hearts in proportion to the decreased workload, thus metabolic efficiency was unaffected. In hearts reperfused following global ischemia, untreated hearts had impaired recovery of LV work (52.3 ± 9.4 %) whereas endotoxemic hearts had significantly higher recovery (105.6 ± 11.3 %, p < 0.05). During reperfusion, fatty acid oxidation, acetyl CoA production and metabolic efficiency were similar in both groups. As impaired cardiac function appeared unrelated to depression of energy substrate oxidation, it is unlikely that drug-induced acceleration of fatty acid oxidation will improve mechanical function. The beneficial repartitioning of glucose metabolism in reperfused endotoxemic hearts may contribute to the cardioprotected phenotype. PMID:26926341

  14. Vinpocetine modulates metabolic activity and function during retinal ischemia.

    PubMed

    Nivison-Smith, Lisa; O'Brien, Brendan J; Truong, Mai; Guo, Cindy X; Kalloniatis, Michael; Acosta, Monica L

    2015-05-01

    Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues. PMID:25696811

  15. Septal and Anterior Reverse Mismatch of Myocardial Perfusion and Metabolism in Patients With Coronary Artery Disease and Left Bundle Branch Block

    PubMed Central

    Wang, Jian-Guang; Fang, Wei; Yang, Min-Fu; Tian, Yue-Qin; Zhang, Xiao-Li; Shen, Rui; Sun, Xiao-Xin; Guo, Feng; Wang, Dao-Yu; He, Zuo-Xiang

    2015-01-01

    Abstract The effects of left bundle branch block (LBBB) on left ventricular myocardial metabolism have not been well investigated. This study evaluated these effects in patients with coronary artery disease (CAD). Sixty-five CAD patients with complete LBBB (mean age, 61.8 ± 9.7 years) and 65 without LBBB (mean age, 59.9 ± 8.4 years) underwent single photon emission computed tomography, positron emission tomography, and contrast coronary angiography. The relationship between myocardial perfusion and metabolism and reverse mismatch score, and that between QRS length and reverse mismatch score and wall motion score were evaluated. The incidence of left ventricular septum and anterior wall reverse mismatching between the two groups was significantly different (P < 0.001 and P = 0.002, respectively). The incidences of normal myocardial perfusion and metabolism in the left ventricular lateral and inferior walls were also significantly different between the two groups (P < 0.001 and P < 0.001, respectively). The incidence of septal reverse mismatching in patients with mild to moderate perfusion was significantly higher among those with LBBB than among those without LBBB (P < 0.001). In CAD patients with LBBB, septal reverse mismatching was significantly more common among those with mild to moderate perfusion than among those with severe perfusion defects (P = 0.002). The correlation between the septal reverse mismatch score and QRS length was significant (P = 0.026). In patients with CAD and LBBB, septal and anterior reverse mismatching of myocardial perfusion and metabolism was frequently present; the septal reverse mismatch score negatively correlated with the QRS interval. PMID:25997045

  16. Factors released from endocardium of the ferret and pig modulate myocardial contraction.

    PubMed Central

    Smith, J A; Shah, A M; Lewis, M J

    1991-01-01

    1. In isolated heart muscle preparations, selective removal of the endocardium results in a characteristic and unusual negative inotropic effect. Possible mechanisms for this effect were investigated in this study. 2. In endocardium-intact preparations of ferret papillary muscle, 8-bromo-cyclic GMP, sodium nitroprusside, atrial natriuretic peptide (ANP) and substance P each induced changes in contractile behaviour similar to selective endocardial removal, and each significantly elevated myocardial cyclic GMP levels. Substance P failed to elevate myocardial cyclic GMP levels following removal of endocardium or in the presence of haemoglobin, suggesting that it may act by releasing endothelium-derived relaxing factor (EDRF) from endocardium. However, there was no change in myocardial cyclic GMP levels following endocardium removal alone. 3. In cascade bioassay experiments, it was confirmed that porcine cultured endocardial cells released an unstable humoral agent whose effects on an endothelium-denuded pig coronary artery were indistinguishable from EDRF. 4. The negative inotropic effects of endocardium removal were reversed in bioassay experiments where an endocardium-denuded papillary muscle was exposed to the effluent from a column of porcine cultured endocardial cells on microcarrier beads. This demonstrates for the first time the release of a 'contraction prolonging factor' from endocardium, the tonic release of which would explain the negative inotropic effect of endocardium removal. 5. It is concluded that elevation of ferret papillary muscle cyclic GMP (as for example with EDRF) produces changes in contractile performance similar to those induced by endocardium removal. We also demonstrate that superfused porcine cultured endocardial cells release a humoral agent (provisionally named 'endocardin') which causes reversal of the changes in mechanical properties seen after endocardial removal. PMID:1716674

  17. Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart

    PubMed Central

    Napoli, Claudio; Cicala, Carla; Wallace, John L.; de Nigris, Filomena; Santagada, Vincenzo; Caliendo, Giuseppe; Franconi, Flavia; Ignarro, Louis J.; Cirino, Giuseppe

    2000-01-01

    Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor α (TNFα) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFα and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFα may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury. PMID:10737808

  18. miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart

    PubMed Central

    Li, Na; Hwangbo, Cheol; Jaba, Irina M.; Zhang, Jiasheng; Papangeli, Irinna; Han, Jinah; Mikush, Nicole; Larrivée, Bruno; Eichmann, Anne; Chun, Hyung J.; Young, Lawrence H.; Tirziu, Daniela

    2016-01-01

    Myocardial hypertrophy is an adaptive response to hemodynamic demands. Although angiogenesis is critical to support the increase in heart mass with matching blood supply, it may also promote a hypertrophic response. Previously, we showed that cardiac angiogenesis induced by placental growth factor (PlGF), promotes myocardial hypertrophy through the paracrine action of endothelium-derived NO, which triggers the degradation of regulator of G protein signaling 4 (RGS4) to activate the Akt/mTORC1 pathways in cardiomyocytes. Here, we investigated whether miRNAs contribute to the development of hypertrophic response associated with myocardial angiogenesis. We show that miR-182 is upregulated concurrently with the development of hypertrophy in PlGF mice, but not when hypertrophy was blocked by concomitant expression of PlGF and RGS4, or by PlGF expression in eNOS−/− mice. Anti-miR-182 treatment inhibits the hypertrophic response and prevents the Akt/mTORC1 activation in PlGF mice and NO-treated cardiomyocytes. miR-182 reduces the expression of Bcat2, Foxo3 and Adcy6 to regulate the hypertrophic response in PlGF mice. Particularly, depletion of Bcat2, identified as a new miR-182 target, promotes AktSer473/p70-S6KThr389 phosphorylation and cardiomyocyte hypertrophy. LV pressure overload did not upregulate miR-182. Thus, miR-182 is a novel target of endothelial-cardiomyocyte crosstalk and plays an important role in the angiogenesis induced-hypertrophic response. PMID:26888314

  19. miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart.

    PubMed

    Li, Na; Hwangbo, Cheol; Jaba, Irina M; Zhang, Jiasheng; Papangeli, Irinna; Han, Jinah; Mikush, Nicole; Larrivée, Bruno; Eichmann, Anne; Chun, Hyung J; Young, Lawrence H; Tirziu, Daniela

    2016-01-01

    Myocardial hypertrophy is an adaptive response to hemodynamic demands. Although angiogenesis is critical to support the increase in heart mass with matching blood supply, it may also promote a hypertrophic response. Previously, we showed that cardiac angiogenesis induced by placental growth factor (PlGF), promotes myocardial hypertrophy through the paracrine action of endothelium-derived NO, which triggers the degradation of regulator of G protein signaling 4 (RGS4) to activate the Akt/mTORC1 pathways in cardiomyocytes. Here, we investigated whether miRNAs contribute to the development of hypertrophic response associated with myocardial angiogenesis. We show that miR-182 is upregulated concurrently with the development of hypertrophy in PlGF mice, but not when hypertrophy was blocked by concomitant expression of PlGF and RGS4, or by PlGF expression in eNOS(-/-) mice. Anti-miR-182 treatment inhibits the hypertrophic response and prevents the Akt/mTORC1 activation in PlGF mice and NO-treated cardiomyocytes. miR-182 reduces the expression of Bcat2, Foxo3 and Adcy6 to regulate the hypertrophic response in PlGF mice. Particularly, depletion of Bcat2, identified as a new miR-182 target, promotes Akt(Ser473)/p70-S6K(Thr389) phosphorylation and cardiomyocyte hypertrophy. LV pressure overload did not upregulate miR-182. Thus, miR-182 is a novel target of endothelial-cardiomyocyte crosstalk and plays an important role in the angiogenesis induced-hypertrophic response. PMID:26888314

  20. Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart.

    PubMed

    Napoli, C; Cicala, C; Wallace, J L; de Nigris, F; Santagada, V; Caliendo, G; Franconi, F; Ignarro, L J; Cirino, G

    2000-03-28

    Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor alpha (TNFalpha) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNFalpha and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNFalpha may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury. PMID:10737808

  1. Modulating the gut flora alters amino acid metabolism in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Intestinal microbes consume and produce amino acids (AA). This may impact intestinal threonine (THR) metabolism necessary for adequate gut function. We hypothesized that modulating the gut flora results in an alteration of intestinal THR utilization and hence whole body AA metabolism. Neonatal pigs ...

  2. LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation.

    PubMed

    Li, Dayuan; Williams, Victor; Liu, Ling; Chen, Hongjiang; Sawamura, Tatsuya; Antakli, Tamim; Mehta, Jawahar L

    2002-11-01

    A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R (P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area (P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size (P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R (P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation (P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury. PMID:12384456

  3. Diet-Induced Metabolic Disturbances As Modulators of Brain Homeostasis

    PubMed Central

    Zhang, Le; Bruce-Keller, Annadora J.; Dasuri, Kalavathi; Nguyen, AnhThao; Liu, Dr Ying; Keller, Jeffrey N.

    2009-01-01

    A number of metabolic disturbances occur in response to the consumption of a high fat Western diet. Such metabolic disturbances can include the progressive development of hyperglycemia, hyperinsulemia, obesity, metabolic syndrome, and diabetes. Cumulatively, diet-induced disturbance in metabolism are known to promote increased morbidity and negatively impact life expectancy through a variety of mechanisms. While the impact of metabolic disturbances on the hepatic, endocrine, and cardiovascular systems are well established there remains a noticeable void in understanding the basis by which the central nervous system (CNS) becomes altered in response to diet-induced metabolic dysfunction. In particular, it remains to be fully elucidated which established features of diet-induced pathogenesis (observed in non-CNS tissues) are recapitulated in the brain, and identification as to whether the observed changes in the brain are a direct or indirect effect of peripheral metabolic disturbances. This review will focus on each of these key issues and identify some critical experimental questions which remain to be elucidated experimentally, as well as provide an outline of our current understanding for how diet-induced alterations in metabolism may impact the brain during aging and age-related diseases of the nervous system. PMID:18926905

  4. Sodium hydrosulfide prevents myocardial dysfunction through modulation of extracellular matrix accumulation and vascular density.

    PubMed

    Pan, Li-Long; Wang, Xian-Li; Wang, Xi-Ling; Zhu, Yi-Zhun

    2014-01-01

    The aim was to examine the role of exogenous hydrogen sulfide (H2S) on cardiac remodeling in post-myocardial infarction (MI) rats. MI was induced in rats by ligation of coronary artery. After treatment with sodium hydrosulfide (NaHS, an exogenous H2S donor, 56 μM/kg·day) for 42 days, the effects of NaHS on left ventricular morphometric features, echocardiographic parameters, heme oxygenase-1 (HO-1), matrix metalloproteinases-9 (MMP-9), type I and type III collagen, vascular endothelial growth factor (VEGF), CD34, and α-smooth muscle actin (α-SMA) in the border zone of infarct area were analyzed to elucidate the protective mechanisms of exogenous H2S on cardiac function and fibrosis. Forty-two days post MI, NaHS-treatment resulted in a decrease in myocardial fibrotic area in association with decreased levels of type I, type III collagen and MMP-9 and improved cardiac function. Meanwhile, NaHS administration significantly increased cystathionine γ-lyase (CSE), HO-1, α-SMA, and VEGF expression. This effect was accompanied by an increase in vascular density in the border zone of infarcted myocardium. Our results provided the strong evidences that exogenous H2S prevented cardiac remodeling, at least in part, through inhibition of extracellular matrix accumulation and increase in vascular density. PMID:25514418

  5. EFFECTS OF CONTINUOUS-WAVE, PULSED, AND SINUSOIDAL-AMPLITUDE-MODULATED MICROWAVES ON BRAIN ENERGY METABOLISM

    EPA Science Inventory

    A comparison of the effects of continuous wave, sinusoidal-amplitude modulated, and pulsed square-wave-modulated 591-MHz microwave exposures on brain energy metabolism was made in male Sprague Dawley rats (175-225g). Brain NADH fluorescence, adensine triphosphate (ATP) concentrat...

  6. Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats.

    PubMed

    Rocha, Juraci Aparecida; Ribeiro, Susan Pereira; França, Cristiane Miranda; Coelho, Otávio; Alves, Gisele; Lacchini, Silvia; Kallás, Esper Georges; Irigoyen, Maria Cláudia; Consolim-Colombo, Fernanda M

    2016-04-15

    We tested the hypothesis that an increase in the anti-inflammatory cholinergic pathway, when induced by pyridostigmine (PY), may modulate subtypes of lymphocytes (CD4+, CD8+, FOXP3+) and macrophages (M1/M2) soon after myocardial infarction (MI) in rats. Wistar rats, randomly allocated to receive PY (40 mg·kg(-1)·day(-1)) in drinking water or to stay without treatment, were followed for 4 days and then were subjected to ligation of the left coronary artery. The groups-denominated as the pyridostigmine-treated infarcted (IP) and infarcted control (I) groups-were submitted to euthanasia 3 days after MI; the heart was removed for immunohistochemistry, and the peripheral blood and spleen were collected for flow cytometry analysis. Noninfarcted and untreated rats were used as controls (C Group). Echocardiographic measurements were registered on the second day after MI, and heart rate variability was measured on the third day after MI. The infarcted groups had similar MI areas, degrees of systolic dysfunction, blood pressures, and heart rates. Compared with the I Group, the IP Group showed a significant higher parasympathetic modulation and a lower sympathetic modulation, which were associated with a small, but significant, increase in diastolic function. The IP Group showed a significant increase in M2 macrophages and FOXP3(+)cells in the infarcted and peri-infarcted areas, a significantly higher frequency of circulating Treg cells (CD4(+)CD25(+)FOXP3(+)), and a less extreme decrease in conventional T cells (CD25(+)FOXP3(-)) compared with the I Group. Therefore, increasing cholinergic modulation with PY induces greater anti-inflammatory cell recruitment soon after MY in rats. PMID:26791829

  7. [Review: plant polyphenols modulate lipid metabolism and related molecular mechanism].

    PubMed

    Dai, Yan-li; Zou, Yu-xiao; Liu, Fan; Li, Hong-zhi

    2015-11-01

    Lipid metabolism disorder is an important risk factor to obesity, hyperlipidemia and type 2 diabetes as well as other chronic metabolic disease. It is also a key target in preventing metabolic syndrome, chronic disease prevention. Plant polyphenol plays an important role in maintaining or improving lipid profile in a variety of ways. including regulating cholesterol absorption, inhibiting synthesis and secretion of triglyceride, and lowering plasma low density lipoprotein oxidation, etc. The purpose of this article is to review the lipid regulation effects of plant polyphenols and its related mechanisms. PMID:27071245

  8. Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: Modulation of cardiac PPAR-{alpha}-mediated transcription of fatty acid metabolic genes

    SciTech Connect

    Huang, Tom H.-W.; Yang Qinglin; Harada, Masaki; Uberai, Jasna; Radford, Jane; Li, George Q.; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao . E-mail: yuhao@pharm.usyd.edu.au

    2006-01-15

    Excess cardiac triglyceride accumulation in diabetes and obesity induces lipotoxicity, which predisposes the myocytes to death. On the other hand, increased cardiac fatty acid (FA) oxidation plays a role in the development of myocardial dysfunction in diabetes. PPAR-{alpha} plays an important role in maintaining homeostasis of lipid metabolism. We have previously demonstrated that the extract from Salacia oblonga root (SOE), an Ayurvedic anti-diabetic and anti-obesity medicine, improves hyperlipidemia in Zucker diabetic fatty (ZDF) rats (a genetic model of type 2 diabetes and obesity) and possesses PPAR-{alpha} activating properties. Here we demonstrate that chronic oral administration of SOE reduces cardiac triglyceride and FA contents and decreases the Oil red O-stained area in the myocardium of ZDF rats, which parallels the effects on plasma triglyceride and FA levels. Furthermore, the treatment suppressed cardiac overexpression of both FA transporter protein-1 mRNA and protein in ZDF rats, suggesting inhibition of increased cardiac FA uptake as the basis for decreased cardiac FA levels. Additionally, the treatment also inhibited overexpression in ZDF rat heart of PPAR-{alpha} mRNA and protein and carnitine palmitoyltransferase-1, acyl-CoA oxidase and 5'-AMP-activated protein kinase mRNAs and restored the downregulated acetyl-CoA carboxylase mRNA. These results suggest that SOE inhibits cardiac FA oxidation in ZDF rats. Thus, our findings suggest that improvement by SOE of excess cardiac lipid accumulation and increased cardiac FA oxidation in diabetes and obesity occurs by reduction of cardiac FA uptake, thereby modulating cardiac PPAR-{alpha}-mediated FA metabolic gene transcription.

  9. Uric acid as a modulator of glucose and lipid metabolism.

    PubMed

    Lima, William Gustavo; Martins-Santos, Maria Emília Soares; Chaves, Valéria Ernestânia

    2015-09-01

    In humans, uric acid is the final oxidation product of purine catabolism. The serum uric acid level is based on the balance between the absorption, production and excretion of purine. Uric acid is similarly produced in the liver, adipose tissue and muscle and is primarily excreted through the urinary tract. Several factors, including a high-fructose diet and the use of xenobiotics and alcohol, contribute to hyperuricaemia. Hyperuricaemia belongs to a cluster of metabolic and haemodynamic abnormalities, called metabolic syndrome, characterised by abdominal obesity, glucose intolerance, insulin resistance, dyslipidaemia and hypertension. Hyperuricaemia reduction in the Pound mouse or fructose-fed rats, as well as hyperuricaemia induction by uricase inhibition in rodents and studies using cell culture have suggested that uric acid plays an important role in the development of metabolic syndrome. These studies have shown that high uric acid levels regulate the oxidative stress, inflammation and enzymes associated with glucose and lipid metabolism, suggesting a mechanism for the impairment of metabolic homeostasis. Humans lacking uricase, the enzyme responsible for uric acid degradation, are susceptible to these effects. In this review, we summarise the current knowledge of the effects of uric acid on the regulation of metabolism, primarily focusing on liver, adipose tissue and skeletal muscle. PMID:26133655

  10. Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function.

    PubMed

    Otto Beitnes, Jan; Oie, Erik; Shahdadfar, Aboulghassem; Karlsen, Tommy; Müller, Regine M B; Aakhus, Svend; Reinholt, Finn P; Brinchmann, Jan E

    2012-01-01

    Cell therapy is a promising treatment modality to improve heart function in acute myocardial infarction. However, the mechanisms of action and the most suitable cell type have not been finally determined. We performed a study to compare the effects of mesenchymal stem cells (MSCs) harvested from different tissues on LV function and explore their effects on tissue structure by morphometry and histological staining for species and lineage relationship. MSCs from skeletal muscle (SM-MSCs) and adipose tissue (ADSCs) were injected in the myocardium of nude rats 1 week after myocardial infarction. After 4 weeks of observation, LVEF was significantly improved in the SM-MSCs group (39.1%) and in the ADSC group (39.6%), compared to the placebo group (31.0%, p < 0.001 for difference in change between groups). Infarct size was smaller after cell therapy (16.3% for SM-MSCs, 15.8% for ADSCs vs. 26.0% for placebo, p < 0.001), and the amount of highly vascularized granulation tissue in the border zone was significantly increased in both groups receiving MSCs (18.3% for SM-MSCs, 22.6% for ADSCs vs. 13.1% for placebo, p = 0.001). By in situ hybridization, moderate engraftment of transplanted cells was found, but no transdifferentiation to cardiomyocytes, endothelial cells, or smooth muscle cells was observed. We conclude that MSC injections lead to improved LVEF after AMI in rats predominantly by reduction of infarct size. After 4 weeks, we observed modulation of scar formation with significant increase in granulation tissue. Transdifferentiation of MSCs to cardiomyocytes or vascular cells did not contribute significantly in this process. MSCs from skeletal muscle and adipose tissue had similar effects. PMID:22410280

  11. Thyroid hormone’s role in regulating brain glucose metabolism and potentially modulating hippocampal cognitive processes

    PubMed Central

    Jahagirdar, V; McNay, EC

    2012-01-01

    Cognitive performance is dependent on adequate glucose supply to the brain. Insulin, which regulates systemic glucose metabolism, has been recently shown both to regulate hippocampal metabolism and to be a mandatory component of hippocampally-mediated cognitive performance. Thyroid hormones (TH) regulate systemic glucose metabolism and may also be involved in regulation of brain glucose metabolism. Here we review potential mechanisms for such regulation. Importantly, TH imbalance is often encountered in combination with metabolic disorders, such as diabetes, and may cause additional metabolic dysregulation and hence worsening of disease states. TH’s potential as a regulator of brain glucose metabolism is heightened by interactions with insulin signaling, but there have been relatively few studies on this topic or on the actions of TH in a mature brain. This review discusses evidence for mechanistic links between TH, insulin, cognitive function, and brain glucose metabolism, and suggests that TH is a good candidate to be a modulator of memory processes, likely at least in part by modulation of central insulin signaling and glucose metabolism. PMID:22437199

  12. Serotonin modulation of cerebral glucose metabolism: sex and age effects.

    PubMed

    Munro, Cynthia A; Workman, Clifford I; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S

    2012-11-01

    The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20-79 years) underwent two resting positron emission tomography studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. PMID:22836227

  13. Dimethyl fumarate modulates antioxidant and lipid metabolism in oligodendrocytes.

    PubMed

    Huang, He; Taraboletti, Alexandra; Shriver, Leah P

    2015-08-01

    Oxidative stress contributes to pathology associated with inflammatory brain disorders and therapies that upregulate antioxidant pathways may be neuroprotective in diseases such as multiple sclerosis. Dimethyl fumarate, a small molecule therapeutic for multiple sclerosis, activates cellular antioxidant signaling pathways and may promote myelin preservation. However, it is still unclear what mechanisms may underlie this neuroprotection and whether dimethyl fumarate affects oligodendrocyte responses to oxidative stress. Here, we examine metabolic alterations in oligodendrocytes treated with dimethyl fumarate by using a global metabolomic platform that employs both hydrophilic interaction liquid chromatography-mass spectrometry and shotgun lipidomics. Prolonged treatment of oligodendrocytes with dimethyl fumarate induces changes in citric acid cycle intermediates, glutathione, and lipids, indicating that this compound can directly impact oligodendrocyte metabolism. These metabolic alterations are also associated with protection from oxidant challenge. This study provides insight into the mechanisms by which dimethyl fumarate could preserve myelin integrity in patients with multiple sclerosis. PMID:25967672

  14. Size matters: plasticity in metabolic scaling shows body-size may modulate responses to climate change.

    PubMed

    Carey, Nicholas; Sigwart, Julia D

    2014-08-01

    Variability in metabolic scaling in animals, the relationship between metabolic rate ( R: ) and body mass ( M: ), has been a source of debate and controversy for decades. R: is proportional to MB: , the precise value of B: much debated, but historically considered equal in all organisms. Recent metabolic theory, however, predicts B: to vary among species with ecology and metabolic level, and may also vary within species under different abiotic conditions. Under climate change, most species will experience increased temperatures, and marine organisms will experience the additional stressor of decreased seawater pH ('ocean acidification'). Responses to these environmental changes are modulated by myriad species-specific factors. Body-size is a fundamental biological parameter, but its modulating role is relatively unexplored. Here, we show that changes to metabolic scaling reveal asymmetric responses to stressors across body-size ranges; B: is systematically decreased under increasing temperature in three grazing molluscs, indicating smaller individuals were more responsive to warming. Larger individuals were, however, more responsive to reduced seawater pH in low temperatures. These alterations to the allometry of metabolism highlight abiotic control of metabolic scaling, and indicate that responses to climate warming and ocean acidification may be modulated by body-size. PMID:25122741

  15. Bone marrow transplantation modulates tissue macrophage phenotype and enhances cardiac recovery after subsequent acute myocardial infarction

    PubMed Central

    Protti, Andrea; Mongue-Din, Heloise; Mylonas, Katie J.; Sirker, Alexander; Sag, Can Martin; Swim, Megan M.; Maier, Lars; Sawyer, Greta; Dong, Xuebin; Botnar, Rene; Salisbury, Jon; Gray, Gillian A.; Shah, Ajay M.

    2016-01-01

    Background Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. Methods and results Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. Conclusions The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI. PMID:26688473

  16. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate tha...

  17. Dopamine Modulates Metabolic Rate and Temperature Sensitivity in Drosophila melanogaster

    PubMed Central

    Ueno, Taro; Tomita, Jun; Kume, Shoen; Kume, Kazuhiko

    2012-01-01

    Homeothermal animals, such as mammals, maintain their body temperature by heat generation and heat dissipation, while poikilothermal animals, such as insects, accomplish it by relocating to an environment of their favored temperature. Catecholamines are known to regulate thermogenesis and metabolic rate in mammals, but their roles in other animals are poorly understood. The fruit fly, Drosophila melanogaster, has been used as a model system for the genetic studies of temperature preference behavior. Here, we demonstrate that metabolic rate and temperature sensitivity of some temperature sensitive behaviors are regulated by dopamine in Drosophila. Temperature-sensitive molecules like dTrpA1 and shits induce temperature-dependent behavioral changes, and the temperature at which the changes are induced were lowered in the dopamine transporter-defective mutant, fumin. The mutant also displays a preference for lower temperatures. This thermophobic phenotype was rescued by the genetic recovery of the dopamine transporter in dopamine neurons. Flies fed with a dopamine biosynthesis inhibitor (3-iodo-L-tyrosine), which diminishes dopamine signaling, exhibited preference for a higher temperature. Furthermore, we found that the metabolic rate is up-regulated in the fumin mutant. Taken together, dopamine has functions in the temperature sensitivity of behavioral changes and metabolic rate regulation in Drosophila, as well as its previously reported functions in arousal/sleep regulation. PMID:22347491

  18. Aging Impairs Myocardial Fatty Acid and Ketone Oxidation and Modifies Cardiac Functional and Metabolic Responses to Insulin in Mice

    SciTech Connect

    Hyyti, Outi M.; Ledee, Dolena; Ning, Xue-Han; Ge, Ming; Portman, Michael A.

    2010-07-02

    Aging presumably initiates shifts in substrate oxidation mediated in part by changes in insulin sensitivity. Similar shifts occur with cardiac hypertrophy and may contribute to contractile dysfunction. We tested the hypothesis that aging modifies substrate utilization and alters insulin sensitivity in mouse heart when provided multiple substrates. In vivo cardiac function was measured with microtipped pressure transducers in the left ventricle from control (4–6 mo) and aged (22–24 mo) mice. Cardiac function was also measured in isolated working hearts along with substrate and anaplerotic fractional contributions to the citric acid cycle (CAC) by using perfusate containing 13C-labeled free fatty acids (FFA), acetoacetate, lactate, and unlabeled glucose. Stroke volume and cardiac output were diminished in aged mice in vivo, but pressure development was preserved. Systolic and diastolic functions were maintained in aged isolated hearts. Insulin prompted an increase in systolic function in aged hearts, resulting in an increase in cardiac efficiency. FFA and ketone flux were present but were markedly impaired in aged hearts. These changes in myocardial substrate utilization corresponded to alterations in circulating lipids, thyroid hormone, and reductions in protein expression for peroxisome proliferator-activated receptor (PPAR)α and pyruvate dehydrogenase kinase (PDK)4. Insulin further suppressed FFA oxidation in the aged. Insulin stimulation of anaplerosis in control hearts was absent in the aged. The aged heart shows metabolic plasticity by accessing multiple substrates to maintain function. However, fatty acid oxidation capacity is limited. Impaired insulin-stimulated anaplerosis may contribute to elevated cardiac efficiency, but may also limit response to acute stress through depletion of CAC intermediates.

  19. Standardized Chinese Formula Xin-Ke-Shu inhibits the myocardium Ca(2+) overloading and metabolic alternations in isoproterenol-induced myocardial infarction rats.

    PubMed

    Liu, Yue-Tao; Zhou, Chao; Jia, Hong-Mei; Chang, Xing; Zou, Zhong-Mei

    2016-01-01

    Xin-Ke-Shu (XKS) is a traditional Chinese patent medicine used for treatment of coronary heart diseases in China. However, its mechanism of action is still unclear. In this paper, the mediation of XKS on the isoproterenol (ISO)-induced myocardial infarction (MI) rat were evaluated based on a tissue-targeted metabonomics in vitro/vivo. The result indicated that twelve metabolic pathways were involved in the therapeutic effect of XKS in vivo, where seven pathways were associated with the Ca(2+) overloading mechanism. In agreement with regulation on metabolic variations, XKS markedly reversed the over-expressions of three involved proteins including phospholipase A2 IIA (PLA2 IIA), calcium/calmodulin-dependent protein kinase II (CaMK II) and Pro-Caspase-3. The metabolic regulations of XKS on H9c2 cell also partially confirmed its metabolic effect. These metabolic characteristics in vitro/vivo and western blotting analysis suggested that XKS protected from MI metabolic perturbation major via inhibition of Ca(2+) overloading mechanism. Furthermore, 11 active ingredients of XKS exerted steady affinity with the three proteins through the molecular docking study. Our findings indicate that the metabonomics in vitro/vivo combined with western blotting analysis offers the opportunity to gain insight into the comprehensive efficacy of TCMs on the whole metabolic network. PMID:27457884

  20. Standardized Chinese Formula Xin-Ke-Shu inhibits the myocardium Ca2+ overloading and metabolic alternations in isoproterenol-induced myocardial infarction rats

    PubMed Central

    Liu, Yue-Tao; Zhou, Chao; Jia, Hong-Mei; Chang, Xing; Zou, Zhong-Mei

    2016-01-01

    Xin-Ke-Shu (XKS) is a traditional Chinese patent medicine used for treatment of coronary heart diseases in China. However, its mechanism of action is still unclear. In this paper, the mediation of XKS on the isoproterenol (ISO)-induced myocardial infarction (MI) rat were evaluated based on a tissue-targeted metabonomics in vitro/vivo. The result indicated that twelve metabolic pathways were involved in the therapeutic effect of XKS in vivo, where seven pathways were associated with the Ca2+ overloading mechanism. In agreement with regulation on metabolic variations, XKS markedly reversed the over-expressions of three involved proteins including phospholipase A2 IIA (PLA2 IIA), calcium/calmodulin-dependent protein kinase II (CaMK II) and Pro-Caspase-3. The metabolic regulations of XKS on H9c2 cell also partially confirmed its metabolic effect. These metabolic characteristics in vitro/vivo and western blotting analysis suggested that XKS protected from MI metabolic perturbation major via inhibition of Ca2+ overloading mechanism. Furthermore, 11 active ingredients of XKS exerted steady affinity with the three proteins through the molecular docking study. Our findings indicate that the metabonomics in vitro/vivo combined with western blotting analysis offers the opportunity to gain insight into the comprehensive efficacy of TCMs on the whole metabolic network. PMID:27457884

  1. New insights on hormones and factors that modulate Sertoli cell metabolism.

    PubMed

    Rato, Luís; Meneses, Maria João; Silva, Branca M; Sousa, Mário; Alves, Marco G; Oliveira, Pedro F

    2016-05-01

    Sertoli cells (SCs) play a key role in spermatogenesis by providing the physical support for developing germ cells and ensuring them the appropriate nutrients, energy sources, hormones, and growth factors. The control of SCs metabolism has been in the spotlight for reproductive biologists, since it may be crucial to determine germ cells' fate. Indeed, the maintenance of spermatogenesis is highly dependent on the metabolic cooperation established between SCs and germ cells, though this event has been overlooked. It depends on the orchestration of various metabolic pathways and an intricate network of signals. Several factors and/or hormones modulate the metabolic activity of SCs, which are major targets for the hormonal signalling that regulates spermatogenesis. Any alteration in the regulation of these cells' metabolic behaviour may compromise the normal development of spermatogenesis and consequently, male fertility. In this context, SC metabolism arises as a key regulation point for spermatogenesis. Herein, we present an up-to-date overview on the impact of hormones and factors that modulate SC metabolism, with special focus on glycolytic metabolism, highlighting their relevance in determining male reproductive potential. PMID:26711246

  2. Coordinated Metabolic Changes and Modulation of Autophagy during Myogenesis.

    PubMed

    Fortini, Paola; Iorio, Egidio; Dogliotti, Eugenia; Isidoro, Ciro

    2016-01-01

    Autophagy undergoes a fine tuning during tissue differentiation and organ remodeling in order to meet the dynamic changes in the metabolic needs. While the involvement of autophagy in the homeostasis of mature muscle tissues has been intensively studied, no study has so far addressed the regulation of autophagy in relation to the metabolic state during the myogenic differentiation. In our recently published study (Fortini et al., 2016) we investigated the metabolic profile and regulation of autophagy that accompany the differentiation process of mouse skeletal muscle satellite cells (MSC)-derived myoblasts into myotubes. Here, we briefly present these findings also in the light of similar studies conducted by other authors. We show that during myogenic differentiation mitochondrial function and activity are greatly increased, and the activation of autophagy accompanies the transition from myoblasts to myotube. Autophagy is mTORC1 inactivation-independent and, remarkably, is required to allow the myocyte fusion process, as shown by impaired cell fusion when the autophagic flux is inhibited either by genetic or drug manipulation. Further, we found that myoblasts derived from p53 null mice show defective terminal differentiation into myotubes and reduced activation of basal autophagy. Of note, glycolysis prevails and mitochondrial biogenesis is strongly impaired in p53-null myoblasts. Thus, autophagy, mitochondrial homeostasis, and differentiation are finely tuned in a coordinate manner during muscle biogenesis. PMID:27378945

  3. Coordinated Metabolic Changes and Modulation of Autophagy during Myogenesis

    PubMed Central

    Fortini, Paola; Iorio, Egidio; Dogliotti, Eugenia; Isidoro, Ciro

    2016-01-01

    Autophagy undergoes a fine tuning during tissue differentiation and organ remodeling in order to meet the dynamic changes in the metabolic needs. While the involvement of autophagy in the homeostasis of mature muscle tissues has been intensively studied, no study has so far addressed the regulation of autophagy in relation to the metabolic state during the myogenic differentiation. In our recently published study (Fortini et al., 2016) we investigated the metabolic profile and regulation of autophagy that accompany the differentiation process of mouse skeletal muscle satellite cells (MSC)-derived myoblasts into myotubes. Here, we briefly present these findings also in the light of similar studies conducted by other authors. We show that during myogenic differentiation mitochondrial function and activity are greatly increased, and the activation of autophagy accompanies the transition from myoblasts to myotube. Autophagy is mTORC1 inactivation-independent and, remarkably, is required to allow the myocyte fusion process, as shown by impaired cell fusion when the autophagic flux is inhibited either by genetic or drug manipulation. Further, we found that myoblasts derived from p53 null mice show defective terminal differentiation into myotubes and reduced activation of basal autophagy. Of note, glycolysis prevails and mitochondrial biogenesis is strongly impaired in p53-null myoblasts. Thus, autophagy, mitochondrial homeostasis, and differentiation are finely tuned in a coordinate manner during muscle biogenesis. PMID:27378945

  4. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    PubMed Central

    Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

    2016-01-01

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions. DOI: http://dx.doi.org/10.7554/eLife.10250.001 PMID:26920219

  5. Leishmania infantum modulates host macrophage mitochondrial metabolism by hijacking the SIRT1-AMPK axis.

    PubMed

    Moreira, Diana; Rodrigues, Vasco; Abengozar, Maria; Rivas, Luis; Rial, Eduardo; Laforge, Mireille; Li, Xiaoling; Foretz, Marc; Viollet, Benoit; Estaquier, Jérôme; Cordeiro da Silva, Anabela; Silvestre, Ricardo

    2015-03-01

    Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. PMID:25738568

  6. Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis

    PubMed Central

    Moreira, Diana; Rodrigues, Vasco; Abengozar, Maria; Rivas, Luis; Rial, Eduardo; Laforge, Mireille; Li, Xiaoling; Foretz, Marc; Viollet, Benoit; Estaquier, Jérôme; Cordeiro da Silva, Anabela; Silvestre, Ricardo

    2015-01-01

    Metabolic manipulation of host cells by intracellular pathogens is currently recognized to play an important role in the pathology of infection. Nevertheless, little information is available regarding mitochondrial energy metabolism in Leishmania infected macrophages. Here, we demonstrate that during L. infantum infection, macrophages switch from an early glycolytic metabolism to an oxidative phosphorylation, and this metabolic deviation requires SIRT1 and LKB1/AMPK. SIRT1 or LBK1 deficient macrophages infected with L. infantum failed to activate AMPK and up-regulate its targets such as Slc2a4 and Ppargc1a, which are essential for parasite growth. As a result, impairment of metabolic switch caused by SIRT1 or AMPK deficiency reduces parasite load in vitro and in vivo. Overall, our work demonstrates the importance of SIRT1 and AMPK energetic sensors for parasite intracellular survival and proliferation, highlighting the modulation of these proteins as potential therapeutic targets for the treatment of leishmaniasis. PMID:25738568

  7. The gut microbiota modulates host amino acid and glutathione metabolism in mice.

    PubMed

    Mardinoglu, Adil; Shoaie, Saeed; Bergentall, Mattias; Ghaffari, Pouyan; Zhang, Cheng; Larsson, Erik; Bäckhed, Fredrik; Nielsen, Jens

    2015-10-01

    The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice. PMID:26475342

  8. The gut microbiota modulates host amino acid and glutathione metabolism in mice

    PubMed Central

    Mardinoglu, Adil; Shoaie, Saeed; Bergentall, Mattias; Ghaffari, Pouyan; Zhang, Cheng; Larsson, Erik; Bäckhed, Fredrik; Nielsen, Jens

    2015-01-01

    The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice. PMID:26475342

  9. AIR-SPAMM: alternative inversion recovery spatial modulation of magnetization for myocardial tagging

    NASA Astrophysics Data System (ADS)

    Aletras, Anthony H.; Freidlin, Raisa Z.; Navon, Gil; Arai, Andrew E.

    2004-02-01

    Alternate inversion recovery spatial modulation of magnetization (AIR-SPAMM) can be used either for doubling the number of tags for a given tagging encoding gradient strength or for improving tagging contrast ratio. AIR-SPAMM requires only a single acquisition and utilizes inversion pulses spaced throughout the gradient recalled echo (GRE) cine acquisition to "lock" the recovering magnetization at a desired level. The theory of AIR-SPAMM is presented along with simulations and results from phantoms. AIR-SPAMM can be used either for imaging systole as demonstrated by initial in vivo results or potentially for imaging the entire cardiac cycle in a slice-interleaved manner.

  10. Lipid metabolizing enzyme activities modulated by phospholipid substrate lateral distribution.

    PubMed

    Salinas, Dino G; Reyes, Juan G; De la Fuente, Milton

    2011-09-01

    Biological membranes contain many domains enriched in phospholipid lipids and there is not yet clear explanation about how these domains can control the activity of phospholipid metabolizing enzymes. Here we used the surface dilution kinetic theory to derive general equations describing how complex substrate distributions affect the activity of enzymes following either the phospholipid binding kinetic model (which assumes that the enzyme molecules directly bind the phospholipid substrate molecules), or the surface-binding kinetic model (which assumes that the enzyme molecules bind to the membrane before binding the phospholipid substrate). Our results strongly suggest that, if the enzyme follows the phospholipid binding kinetic model, any substrate redistribution would increase the enzyme activity over than observed for a homogeneous distribution of substrate. Besides, enzymes following the surface-binding model would be independent of the substrate distribution. Given that the distribution of substrate in a population of micelles (each of them a lipid domain) should follow a Poisson law, we demonstrate that the general equations give an excellent fit to experimental data of lipases acting on micelles, providing reasonable values for kinetic parameters--without invoking special effects such as cooperative phenomena. Our theory will allow a better understanding of the cellular-metabolism control in membranes, as well as a more simple analysis of the mechanisms of membrane acting enzymes. PMID:21108012

  11. Metabolic Flux Ratio Analysis of Genetic and Environmental Modulations of Escherichia coli Central Carbon Metabolism

    PubMed Central

    Sauer, Uwe; Lasko, Daniel R.; Fiaux, Jocelyne; Hochuli, Michel; Glaser, Ralf; Szyperski, Thomas; Wüthrich, Kurt; Bailey, James E.

    1999-01-01

    The response of Escherichia coli central carbon metabolism to genetic and environmental manipulation has been studied by use of a recently developed methodology for metabolic flux ratio (METAFoR) analysis; this methodology can also directly reveal active metabolic pathways. Generation of fluxome data arrays by use of the METAFoR approach is based on two-dimensional 13C-1H correlation nuclear magnetic resonance spectroscopy with fractionally labeled biomass and, in contrast to metabolic flux analysis, does not require measurements of extracellular substrate and metabolite concentrations. METAFoR analyses of E. coli strains that moderately overexpress phosphofructokinase, pyruvate kinase, pyruvate decarboxylase, or alcohol dehydrogenase revealed that only a few flux ratios change in concert with the overexpression of these enzymes. Disruption of both pyruvate kinase isoenzymes resulted in altered flux ratios for reactions connecting the phosphoenolpyruvate (PEP) and pyruvate pools but did not significantly alter central metabolism. These data indicate remarkable robustness and rigidity in central carbon metabolism in the presence of genetic variation. More significant physiological changes and flux ratio differences were seen in response to altered environmental conditions. For example, in ammonia-limited chemostat cultures, compared to glucose-limited chemostat cultures, a reduced fraction of PEP molecules was derived through at least one transketolase reaction, and there was a higher relative contribution of anaplerotic PEP carboxylation than of the tricarboxylic acid (TCA) cycle for oxaloacetate synthesis. These two parameters also showed significant variation between aerobic and anaerobic batch cultures. Finally, two reactions catalyzed by PEP carboxykinase and malic enzyme were identified by METAFoR analysis; these had previously been considered absent in E. coli cells grown in glucose-containing media. Backward flux from the TCA cycle to glycolysis, as

  12. Myocardial Gene Transfer: Routes and Devices for Regulation of Transgene Expression by Modulation of Cellular Permeability

    PubMed Central

    Katz, Michael G.; Bridges, Charles R.

    2013-01-01

    Abstract Heart diseases are major causes of morbidity and mortality in Western society. Gene therapy approaches are becoming promising therapeutic modalities to improve underlying molecular processes affecting failing cardiomyocytes. Numerous cardiac clinical gene therapy trials have yet to demonstrate strong positive results and advantages over current pharmacotherapy. The success of gene therapy depends largely on the creation of a reliable and efficient delivery method. The establishment of such a system is determined by its ability to overcome the existing biological barriers, including cellular uptake and intracellular trafficking as well as modulation of cellular permeability. In this article, we describe a variety of physical and mechanical methods, based on the transient disruption of the cell membrane, which are applied in nonviral gene transfer. In addition, we focus on the use of different physiological techniques and devices and pharmacological agents to enhance endothelial permeability. Development of these methods will undoubtedly help solve major problems facing gene therapy. PMID:23427834

  13. Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism.

    PubMed

    Wartchow, Krista Minéia; Tramontina, Ana Carolina; de Souza, Daniela F; Biasibetti, Regina; Bobermin, Larissa D; Gonçalves, Carlos-Alberto

    2016-06-01

    Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B. PMID:26875731

  14. Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases

    PubMed Central

    Jung, Tae Woo; Choi, Kyung Mook

    2016-01-01

    The endoplasmic reticulum (ER) is the principal organelle responsible for correct protein folding, a step in protein synthesis that is critical for the functional conformation of proteins. ER stress is a primary feature of secretory cells and is involved in the pathogenesis of numerous human diseases, such as certain neurodegenerative and cardiometabolic disorders. The unfolded protein response (UPR) is a defense mechanism to attenuate ER stress and maintain the homeostasis of the organism. Two major degradation systems, including the proteasome and autophagy, are involved in this defense system. If ER stress overwhelms the capacity of the cell’s defense mechanisms, apoptotic death may result. This review is focused on the various pharmacological modulators that can protect cells from damage induced by ER stress. The possible mechanisms for cytoprotection are also discussed. PMID:26840310

  15. Polyamine acetylation modulates polyamine metabolic flux, a prelude to broader metabolic consequences.

    PubMed

    Kramer, Debora L; Diegelman, Paula; Jell, Jason; Vujcic, Slavoljub; Merali, Salim; Porter, Carl W

    2008-02-15

    Recent studies suggest that overexpression of the polyamine-acetylating enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) significantly increases metabolic flux through the polyamine pathway. The concept derives from the observation that SSAT-induced acetylation of polyamines gives rise to a compensatory increase in biosynthesis and presumably to increased flow through the pathway. Despite the strength of this deduction, the existence of heightened polyamine flux has not yet been experimentally demonstrated. Here, we use the artificial polyamine precursor 4-fluoro-ornithine to measure polyamine flux by tracking fluorine unit permeation of polyamine pools in human prostate carcinoma LNCaP cells. Conditional overexpression of SSAT was accompanied by a massive increase in intracellular and extracellular acetylated spermidine and by a 6-20-fold increase in biosynthetic enzyme activities. In the presence of 300 microM 4-fluoro-ornithine, SSAT overexpression led to the sequential appearance of fluorinated putrescine, spermidine, acetylated spermidine, and spermine. As fluorinated polyamines increased, endogenous polyamines decreased, so that the total polyamine pool size remained relatively constant. At 24 h, 56% of the spermine pool in the induced SSAT cells was fluorine-labeled compared with only 12% in uninduced cells. Thus, SSAT induction increased metabolic flux by approximately 5-fold. Flux could be interrupted by inhibition of polyamine biosynthesis but not by inhibition of polyamine oxidation. Overall, the findings are consistent with a paradigm whereby flux is initiated by SSAT acetylation of spermine and particularly spermidine followed by a marked increase in key biosynthetic enzymes. The latter sustains the flux cycle by providing a constant supply of polyamines for subsequent acetylation by SSAT. The broader metabolic implications of this futile metabolic cycling are discussed in detail. PMID:18089555

  16. Light quality modulates metabolic synchronization over the diel phases of crassulacean acid metabolism.

    PubMed

    Ceusters, Johan; Borland, Anne M; Taybi, Tahar; Frans, Mario; Godts, Christof; De Proft, Maurice P

    2014-07-01

    Temporal compartmentation of carboxylation processes is a defining feature of crassulacean acid metabolism and involves circadian control of key metabolic and transport steps that regulate the supply and demand for carbon over a 24h cycle. Recent insights on the molecular workings of the circadian clock and its connection with environmental inputs raise new questions on the importance of light quality and, by analogy, certain photoreceptors for synchronizing the metabolic components of CAM. The present work tested the hypothesis that optimal coupling of stomatal conductance, net CO2 uptake, and the reciprocal turnover of carbohydrates and organic acids over the diel CAM cycle requires both blue and red light input signals. Contrasting monochromatic wavelengths of blue, green, and red light (i.e. 475, 530, 630nm) with low fluence rates (10 μmol m(-2) s(-1)) were administered for 16 hours each diel cycle for a total treatment time of 48 hours to the obligate CAM bromeliad, Aechmea 'Maya'. Of the light treatments imposed, low-fluence blue light was a key determinant in regulating stomatal responses, organic acid mobilization from the vacuole, and daytime decarboxylation. However, the reciprocal relationship between starch and organic acid turnover that is typical for CAM was uncoupled under low-fluence blue light. Under low-fluence red or green light, the diel turnover of storage carbohydrates was orchestrated in line with the requirements of CAM, but a consistent delay in acid consumption at dawn compared with plants under white or low-fluence blue light was noted. Consistent with the acknowledged influences of both red and blue light as input signals for the circadian clock, the data stress the importance of both red and blue-light signalling pathways for synchronizing the metabolic and physiological components of CAM over the day/night cycle. PMID:24803500

  17. Light quality modulates metabolic synchronization over the diel phases of crassulacean acid metabolism

    PubMed Central

    Ceusters, Johan; Borland, Anne M.; Taybi, Tahar; Frans, Mario; Godts, Christof; De Proft, Maurice P.

    2014-01-01

    Temporal compartmentation of carboxylation processes is a defining feature of crassulacean acid metabolism and involves circadian control of key metabolic and transport steps that regulate the supply and demand for carbon over a 24h cycle. Recent insights on the molecular workings of the circadian clock and its connection with environmental inputs raise new questions on the importance of light quality and, by analogy, certain photoreceptors for synchronizing the metabolic components of CAM. The present work tested the hypothesis that optimal coupling of stomatal conductance, net CO2 uptake, and the reciprocal turnover of carbohydrates and organic acids over the diel CAM cycle requires both blue and red light input signals. Contrasting monochromatic wavelengths of blue, green, and red light (i.e. 475, 530, 630nm) with low fluence rates (10 μmol m–2 s–1) were administered for 16 hours each diel cycle for a total treatment time of 48 hours to the obligate CAM bromeliad, Aechmea ‘Maya’. Of the light treatments imposed, low-fluence blue light was a key determinant in regulating stomatal responses, organic acid mobilization from the vacuole, and daytime decarboxylation. However, the reciprocal relationship between starch and organic acid turnover that is typical for CAM was uncoupled under low-fluence blue light. Under low-fluence red or green light, the diel turnover of storage carbohydrates was orchestrated in line with the requirements of CAM, but a consistent delay in acid consumption at dawn compared with plants under white or low-fluence blue light was noted. Consistent with the acknowledged influences of both red and blue light as input signals for the circadian clock, the data stress the importance of both red and blue-light signalling pathways for synchronizing the metabolic and physiological components of CAM over the day/night cycle. PMID:24803500

  18. Ecology Drives the Distribution of Specialized Tyrosine Metabolism Modules in Fungi

    PubMed Central

    Greene, George H.; McGary, Kriston L.; Rokas, Antonis; Slot, Jason C.

    2014-01-01

    Gene clusters encoding accessory or environmentally specialized metabolic pathways likely play a significant role in the evolution of fungal genomes. Two such gene clusters encoding enzymes associated with the tyrosine metabolism pathway (KEGG #00350) have been identified in the filamentous fungus Aspergillus fumigatus. The l-tyrosine degradation (TD) gene cluster encodes a functional module that facilitates breakdown of the phenolic amino acid, l-tyrosine through a homogentisate intermediate, but is also involved in the production of pyomelanin, a fungal pathogenicity factor. The gentisate catabolism (GC) gene cluster encodes a functional module likely involved in phenolic compound degradation, which may enable metabolism of biphenolic stilbenes in multiple lineages. Our investigation of the evolution of the TD and GC gene clusters in 214 fungal genomes revealed spotty distributions partially shaped by gene cluster loss and horizontal gene transfer (HGT). Specifically, a TD gene cluster shows evidence of HGT between the extremophilic, melanized fungi Exophiala dermatitidis and Baudoinia compniacensis, and a GC gene cluster shows evidence of HGT between Sordariomycete and Dothideomycete grass pathogens. These results suggest that the distribution of specialized tyrosine metabolism modules is influenced by both the ecology and phylogeny of fungal species. PMID:24391152

  19. Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients.

    PubMed

    Moreno-Indias, Isabel; Sánchez-Alcoholado, Lidia; Pérez-Martínez, Pablo; Andrés-Lacueva, Cristina; Cardona, Fernando; Tinahones, Francisco; Queipo-Ortuño, María Isabel

    2016-04-01

    This study evaluated the possible prebiotic effect of a moderate intake of red wine polyphenols on the modulation of the gut microbiota composition and the improvement in the risk factors for the metabolic syndrome in obese patients. Ten metabolic syndrome patients and ten healthy subjects were included in a randomized, crossover, controlled intervention study. After a washout period, the subjects consumed red wine and de-alcoholized red wine over a 30 day period for each. The dominant bacterial composition did not differ significantly between the study groups after the two red wine intake periods. In the metabolic syndrome patients, red wine polyphenols significantly increased the number of fecal bifidobacteria and Lactobacillus (intestinal barrier protectors) and butyrate-producing bacteria (Faecalibacterium prausnitzii and Roseburia) at the expense of less desirable groups of bacteria such as LPS producers (Escherichia coli and Enterobacter cloacae). The changes in gut microbiota in these patients could be responsible for the improvement in the metabolic syndrome markers. Modulation of the gut microbiota by using red wine could be an effective strategy for managing metabolic diseases associated with obesity. PMID:26599039

  20. Experimental study on trace chemical contaminant generation rates of human metabolism in spacecraft crew module

    NASA Astrophysics Data System (ADS)

    Lihua, Guo; Xinxing, He; Guoxin, Xu; Xin, Qi

    2012-12-01

    Trace chemical contaminants generated by human metabolism is a major source of contamination in spacecraft crew module. In this research, types and generation rates of pollutants from human metabolism were determined in the Chinese diets. Expired air, skin gas, and sweat of 20 subjects were analyzed at different exercise states in a simulated module. The exercise states were designed according to the basic activities in the orbit of astronauts. Qualitative and quantitative analyses of contaminants generated by human metabolic were performed with gas chromatography/mass spectrometry, gas chromatography and UV spectrophotometer. Sixteen chemical compounds from metabolic sources were found. With the increase in physical load, the concentrations of chemical compounds from human skin and expired air correspondingly increased. The species and the offgassing rates of pollutants from human metabolism are different among the Chinese, Americans and the Russians due to differences in ethnicity and dietary customs. This research provides data to aid in the design, development and operation of China's long duration space mission.

  1. Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

    PubMed

    Iwata, Junichi; Suzuki, Akiko; Pelikan, Richard C; Ho, Thach-Vu; Sanchez-Lara, Pedro A; Chai, Yang

    2014-01-01

    Mutations in transforming growth factor beta (TGFβ) receptor type II (TGFBR2) cause Loeys-Dietz syndrome, characterized by craniofacial and cardiovascular abnormalities. Mice with a deletion of Tgfbr2 in cranial neural crest cells (Tgfbr2(fl/fl);Wnt1-Cre mice) develop cleft palate as the result of abnormal TGFβ signaling activation. However, little is known about metabolic processes downstream of TGFβ signaling during palatogenesis. Here, we show that Tgfbr2 mutant palatal mesenchymal cells spontaneously accumulate lipid droplets, resulting from reduced lipolysis activity. Tgfbr2 mutant palatal mesenchymal cells failed to respond to the cell proliferation stimulator sonic hedgehog, derived from the palatal epithelium. Treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor or telmisartan, a modulator of p38 MAPK activation and lipid metabolism, blocked abnormal TGFβ-mediated p38 MAPK activation, restoring lipid metabolism and cell proliferation activity both in vitro and in vivo. Our results highlight the influence of alternative TGFβ signaling on lipid metabolic activities, as well as how lipid metabolic defects can affect cell proliferation and adversely impact palatogenesis. This discovery has broader implications for the understanding of metabolic defects and potential prevention of congenital birth defects. PMID:23975680

  2. A preliminary feasibility study of simultaneous dual-isotope imaging with a solid-state dedicated cardiac camera for evaluating myocardial perfusion and fatty acid metabolism.

    PubMed

    Ko, Toshiyuki; Utanohara, Yuko; Suzuki, Yasuhiro; Kurihara, Makiko; Iguchi, Nobuo; Umemura, Jun; Sumiyoshi, Tetsuya; Tomoike, Hitonobu

    2016-01-01

    Simultaneous dual-isotope SPECT imaging with 201Tl and (123)I-β-methyl-p-iodophenylpentadecanoic acid (BMIPP) is used to study the perfusion-metabolism mismatch. It predicts post-ischemic functional recovery by detecting stunned myocardium. On the other hand, (99m)Tc-MIBI is another radioisotope widely used in myocardial perfusion imaging because of its better image quality and lower radiation exposure than 201Tl. However, since the photopeak energies of (99m)Tc and (123)I are very similar, crosstalk hampers the simultaneous use of these two radioisotopes. To overcome this problem, we conducted simultaneous dual-isotope imaging study using the D-SPECT scanner (Spectrum-Dynamics, Israel) which has a novel detector design and excellent energy resolution. We first conducted a basic experiment using cardiac phantom to simulate the condition of normal perfusion and impaired fatty acid metabolism. Subsequently, we prospectively recruited 30 consecutive patients who underwent successful percutaneous coronary intervention for acute myocardial infarction, and performed (99m)Tc-MIBI/(123)I-BMIPP dual-isotope imaging within 5 days after reperfusion. Images were interpreted by two experienced cardiovascular radiologists to identify the infarcted and stunned areas based on the coronary artery territories. As a result, cardiac phantom experiment revealed no significant crosstalk between (99m)Tc and (123)I. In the subsequent clinical study, (99m)Tc-MIBI/(123)I-BMIPP dual-isotope imaging in all participant yielded excellent image quality and detected infarcted and stunned areas correctly when compared with coronary angiographic findings. Furthermore, we were able to reduce radiation exposure to significantly approximately one-eighth. In conclusion, we successfully demonstrated the practical application of simultaneous assessment of myocardial perfusion and fatty acid metabolism by (99m)Tc-MIBI and (123)I-BMIPP using a D-SPECT cardiac scanner. Compared with conventional (201)Tl

  3. Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum

    PubMed Central

    2012-01-01

    Background Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurable metabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and

  4. Protective role of 5-azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis

    PubMed Central

    Kim, Yong Sook; Kang, Wan Seok; Kwon, Jin Sook; Hong, Moon Hwa; Jeong, Hye-yun; Jeong, Hae Chang; Jeong, Myung Ho; Ahn, Youngkeun

    2014-01-01

    We examined whether a shift in macrophage phenotype could be therapeutic for myocardial infarction (MI). The mouse macrophage cell line RAW264.7 was stimulated with peptidoglycan (PGN), with or without 5-azacytidine (5AZ) treatment. MI was induced by ligation of the left anterior descending coronary artery in rats, and the rats were divided into two groups; a saline-injection group and a 5AZ-injection group (2.5 mg/kg/day, intraperitoneal injection). LV function was evaluated and immunohistochemical analyses were performed 2 weeks after MI. Cardiac fibrosis was induced by angiotensin II (AngII) infusion with or without 5AZ (5 mg/kg/day) in mice. Nitric oxide was produced by PGN, which was reduced by 77.87% after 5AZ treatment. Both induction of inducible nitric oxide synthase (iNOS) and iNOS promoter activity by PGN were inhibited by 5AZ. Ejection fraction (59.00 ± 8.03% versus 42.52 ± 2.58%), contractility (LV dP/dt-max, 8299.76 ± 411.56 mmHg versus 6610.36 ± 282.37 mmHg) and relaxation indices (LV dP/dt-min, −4661.37 ± 210.73 mmHg versus −4219.50 ± 162.98 mmHg) were improved after 5AZ administration. Cardiac fibrosis in the MI+5AZ was 8.14 ± 1.00%, compared with 14.93 ± 2.98% in the MI group (P < 0.05). Arginase-1(+)CD68(+) macrophages with anti-inflammatory phenotype were predominant in the infarct border zone of the MI+5AZ group, in comparison with the MI group. AngII-induced cardiac fibrosis was also attenuated after 5AZ administration. In cardiac fibroblasts, pro-fibrotic mediators and cell proliferation were increased by AngII, and these increases were attenuated after 5AZ treatment. 5AZ exerts its cardiac protective role through modulation of macrophages and cardiac fibroblasts. PMID:24571348

  5. Protective role of 5-azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis.

    PubMed

    Kim, Yong Sook; Kang, Wan Seok; Kwon, Jin Sook; Hong, Moon Hwa; Jeong, Hye-Yun; Jeong, Hae Chang; Jeong, Myung Ho; Ahn, Youngkeun

    2014-06-01

    We examined whether a shift in macrophage phenotype could be therapeutic for myocardial infarction (MI). The mouse macrophage cell line RAW264.7 was stimulated with peptidoglycan (PGN), with or without 5-azacytidine (5AZ) treatment. MI was induced by ligation of the left anterior descending coronary artery in rats, and the rats were divided into two groups; a saline-injection group and a 5AZ-injection group (2.5 mg/kg/day, intraperitoneal injection). LV function was evaluated and immunohistochemical analyses were performed 2 weeks after MI. Cardiac fibrosis was induced by angiotensin II (AngII) infusion with or without 5AZ (5 mg/kg/day) in mice. Nitric oxide was produced by PGN, which was reduced by 77.87% after 5AZ treatment. Both induction of inducible nitric oxide synthase (iNOS) and iNOS promoter activity by PGN were inhibited by 5AZ. Ejection fraction (59.00 ± 8.03% versus 42.52 ± 2.58%), contractility (LV dP/dt-max, 8299.76 ± 411.56 mmHg versus 6610.36 ± 282.37 mmHg) and relaxation indices (LV dP/dt-min, -4661.37 ± 210.73 mmHg versus -4219.50 ± 162.98 mmHg) were improved after 5AZ administration. Cardiac fibrosis in the MI+5AZ was 8.14 ± 1.00%, compared with 14.93 ± 2.98% in the MI group (P < 0.05). Arginase-1(+)CD68(+) macrophages with anti-inflammatory phenotype were predominant in the infarct border zone of the MI+5AZ group, in comparison with the MI group. AngII-induced cardiac fibrosis was also attenuated after 5AZ administration. In cardiac fibroblasts, pro-fibrotic mediators and cell proliferation were increased by AngII, and these increases were attenuated after 5AZ treatment. 5AZ exerts its cardiac protective role through modulation of macrophages and cardiac fibroblasts. PMID:24571348

  6. Dietary Isoflavones as Modulators of Drug Metabolizing Enzymes and Transporters: Effect on Prescription Medicines.

    PubMed

    Taneja, Isha; Raju, Kanumuri Siva Rama; Wahajuddin, Muhammad

    2016-07-29

    Isoflavones are the most widely consumed phytoestrogens. Besides being a dietary constituent, their consumption has been increasing in the form of herbal supplements and as promising alternatives to hormonal replacement therapy, in conjunction with prescription medicines. Isoflavones are extensively metabolized by phase I and II enzymes and are substrates of drug transporters. At high concentrations isoflavones may interact with drug metabolizing enzymes and drug transporters and modulate their activity, thus, altering the absorption, metabolism, distribution, excretion and toxicity profile of the co-administered drugs. This review summarizes the up-to-date literature of isoflavone-drug interactions giving insight into the possible mechanisms of interactions, in vitro-in vivo correlation and their implications on clinical outcomes. PMID:26561312

  7. /sup 13/N-labeled L-amino acids for in vivo assessment of local myocardial metabolism

    SciTech Connect

    Baumgartner, F.J.; Barrio, J.R.; Henze, E.; Schelbert, H.R.; MacDonald, N.S.; Phelps, M.E.; Kuhl, D.E.

    1981-06-01

    The hot cell synthesis of sterile, pyrogen-free /sup 13/N-labeled L-amino acids was accomplished by employing the appropriate immobilized enzymes on a CNBr-activated Sepharose support and using remote, semiautomated systems. The syntheses were completed 6-12 min after cyclotron production of (/sup 13/N)ammonia. Myocardial time-activity curves after intracoronary injection of /sup 13/N-labeled L-amino acids in dogs were triexponential in both normal and ischemic myocardium. Higher retention of /sup 13/N activity was observed in ischemic segments. Positron computed tomography imaging also showed increased uptake of /sup 13/N-labeled L-glutamate and L-alanine in ischemic segments compared with normal myocardium when blood flow corrections were made. Myocardial transaminases are primarily responsible for the observed retention fractions. It suggests the participation of the carbon skeletons of these amino acids in the Krebs cycle.

  8. Comparative analysis of changes of myocardial angiogenesis and energy metabolism in postinfarction and diabetic damage of rat heart.

    PubMed

    Afanasiev, Sergey A; Egorova, Margarita V; Kondratyeva, Dina S; Batalov, Roman E; Popov, Sergey V

    2014-01-01

    Comparative study of changes in myocardial activity of lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), and capillary density distribution in the experimental models of diabetic and postinfarction damage of rat heart was performed. Data showed that decrease in LDH and SDH activities was observed in both pathologies which can suggest abnormal processes of glycolysis and oxidative phosphorylation in cardiac mitochondria. Activity of LDH and SDH in combined pathologies was comparative with the corresponding values of these parameters in control group. The authors hypothesize that these differences can be caused by specifics of myocardial vascularization. The results of the study showed that an increase in capillary density was found in all groups of rats with pathologies compared with control group. However, no significant differences in the intensity of angiogenesis processes were found between groups with pathologies. PMID:24689068

  9. Plasma Metabolic Profile Determination in Young ST-segment Elevation Myocardial Infarction Patients with Ischemia and Reperfusion: Ultra-performance Liquid Chromatography and Mass Spectrometry for Pathway Analysis

    PubMed Central

    Huang, Lei; Li, Tong; Liu, Ying-Wu; Zhang, Lei; Dong, Zhi-Huan; Liu, Shu-Ye; Gao, Ying-Tang

    2016-01-01

    Background: This study was to establish a disease differentiation model for ST-segment elevation myocardial infarction (STEMI) youth patients experiencing ischemia and reperfusion via ultra-performance liquid chromatography and mass spectrometry (UPLC/MS) platform, which searches for closely related characteristic metabolites and metabolic pathways to evaluate their predictive value in the prognosis after discharge. Methods: Forty-seven consecutive STEMI patients (23 patients under 45 years of age, referred to here as “youth,” and 24 “elderly” patients) and 48 healthy control group members (24 youth, 24 elderly) were registered prospectively. The youth patients were required to provide a second blood draw during a follow-up visit one year after morbidity (n = 22, one lost). Characteristic metabolites and relative metabolic pathways were screened via UPLC/MS platform base on the Kyoto encyclopedia of genes and genomes (KEGG) and Human Metabolome Database. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of characteristic metabolites in the prognosis after discharge. Results: We successfully established an orthogonal partial least squares discriminated analysis model (R2X = 71.2%, R2Y = 79.6%, and Q2 = 55.9%) and screened out 24 ions; the sphingolipid metabolism pathway showed the most drastic change. The ROC curve analysis showed that ceramide [Cer(d18:0/16:0), Cer(t18:0/12:0)] and sphinganine in the sphingolipid pathway have high sensitivity and specificity on the prognosis related to major adverse cardiovascular events after youth patients were discharged. The area under curve (AUC) was 0.671, 0.750, and 0.711, respectively. A follow-up validation one year after morbidity showed corresponding AUC of 0.778, 0.833, and 0.806. Conclusions: By analyzing the plasma metabolism of myocardial infarction patients, we successfully established a model that can distinguish two different factors simultaneously: pathological

  10. Alterations in myocardial metabolism and function at rest in stable angina pectoris: relations with the amount of exercise-induced thallium-201 perfusion defect

    SciTech Connect

    De Kock, M.; Melin, J.A.; Pouleur, H.; Rousseau, M.F.

    1986-01-01

    The relation between the amount of exercise-induced ischemia and alterations in left ventricular (LV) function and metabolism at rest was studied in 18 coronary patients with stable angina pectoris. An ischemic defect area score was computed from quantitative exercise thallium-201 (Tl-201) scintigraphy; this estimation of the amount of ischemic myocardium was used to classify the patients in group I (n = 8; score less than 15%, mean 6.7 +/- 2.5%) and II (n = 10; score greater than 15%; mean 27.2 +/- 8.9%). Hemodynamics and metabolism were studied in basal state. No patient had anginal pain during the study, and the extent of angiographic coronary artery disease (CAD) was comparable in the two groups. Heart rate, aortic pressure, coronary blood flow, and myocardial oxygen uptake were also similar in both groups. However, ejection fraction was reduced in group II (51 +/- 13 vs 63 +/- 5%; p less than 0.01) and LV relaxation was impaired as shown by the increase in time-constant of isovolumic pressure fall (55 +/- 16 vs 44 +/- 6 ms in group I; p less than 0.05); the LV end-diastolic pressure was also increased in group II (19 +/- 8 vs 10 +/- 4 mmHg in group l; p less than 0.05). Furthermore, in group II, myocardial lactate uptake was reduced (4 +/- 19 vs 30 +/- 29 mumole/min in group I; p less than 0.01) and the productions of alanine and glutamine were augmented (-7.5 +/- 4.4 vs -4.6 +/- 1.6 mumole/min in group I; p less than 0.05).

  11. miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle.

    PubMed

    Zhang, Duo; Li, Yan; Yao, Xuan; Wang, Hui; Zhao, Lei; Jiang, Haowen; Yao, Xiaohan; Zhang, Shengjie; Ye, Cheng; Liu, Wei; Cao, Hongchao; Yu, Shuxian; Wang, Yu-Cheng; Li, Qiong; Jiang, Jingjing; Liu, Yi; Zhang, Ling; Liu, Yun; Iwai, Naoharu; Wang, Hui; Li, Jingya; Li, Jia; Li, Xihua; Jin, Zi-Bing; Ying, Hao

    2016-07-19

    Understanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control. PMID:27396327

  12. A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism.

    PubMed

    Ioannides, Costas; Konsue, Nattaya

    2015-08-01

    Isothiocyanates are small molecules characterized by high chemical reactivity that allows them to interact readily with cellular constituents eliciting a plethora of biological activities. They are present exclusively in cruciferous vegetables, as glucosinolates, the intake of which has been associated with cancer chemoprevention. When the physical structure of these vegetables is disturbed, e.g. during mastication, the enzyme myrosinase is released and converts the glucosinolates to isothiocyanates (R-N=C=S), where R can be aliphatic or aromatic. Although sulforaphane, an aliphatic isothiocyanate, has received most attention worldwide, the most extensively studied aromatic isothiocyanate is phenethyl isothiocyanate (PEITC), and there are substantial differences in biological activity between the two sub-classes. In animal cancer models, PEITC effectively antagonized the carcinogenicity of chemicals, especially nitrosocompounds. A principal mechanism of their action is to protect the integrity of DNA by decreasing the levels of the genotoxic metabolites of chemical carcinogens. Extensive studies established that PEITC modulates the metabolism of the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by inhibiting its cytochrome P450-mediated bioactivation. Moreover, PEITC is a potent inducer of detoxification enzymes such as quinone reductase, glutathione S-transferase and glucuronosyl transferase. PEITC is rapidly absorbed and is characterized by a large bioavailability; Cmax concentrations achieved in plasma after dietary intake are sufficient to modulate carcinogen metabolism. PEITC is primarily metabolized by glutathione conjugation and is excreted in the urine and bile as the mercapturate. The ability of PEITC to perturb carcinogen metabolism through modulation of cytochrome P450 and phase II detoxification enzymes is comprehensively and critically reviewed. PMID:26119477

  13. Effects of catecholamines on rat myocardial metabolism. II. Influence of catecholamines on 32p-incorporation into rat myocardial adenylic nucleotides and their turn-over.

    PubMed

    Merouze, P; Gaudemer, Y; Gautheron, D

    1975-01-01

    1. The influence of catecholamines (adrenaline and noradrenaline) on 32Pi incorporation into intracellular phosphate and adenylic nucleotides has been studied on rat myocardium slices; consequently, the turn-over of nucleotides could be determined and compared under the influence of these two hormones. 2. In order to specify the site of action of these catecholamines, several inhibitors and activators of energetic metabolism were included in the incubation medium: 3'5'-AMP, caffein, ouabain, oligomycin, rotenone + antimycin. 3. Both catecholamines favour Pi exchanges between intra and extracellular spaces; ATP turn-over is greatly increased, while ADP turn-over is slightly decreased, and 32P-incorporation into ADP is increased. 4. 3'5'-AMP and caffein are without effect on Pi penetration; however, caffein increases catecholamine effects on this penetration. ATP turn-over is slightly increased by 3'5'-AMP or caffein. 5. Ouabain decreases ATP turn-over but does not prevent the adrenaline induced acceleration. Inhibitors of oxidative phosphorylation and electron transport decrease ATP-turn-over severely; this inhibition is not released by catecholamines. 6. It is concluded that the catecholamine effects observed are dependent on the oxidative phosphorylations process. The increase of Pi exchange by catecholamines may be related to the increase of extracellular space and cation translocations we observed with the hormones. PMID:173417

  14. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

    SciTech Connect

    Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska; Levels, Johannes H.M.; Quax, Paul H.A.; Meijers, Joost C.M.; Pannekoek, Hans; Groen, Albert K.; Vries, Carlie J.M. de

    2008-02-22

    NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity.

  15. System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia

    PubMed Central

    Zhu, Yan; Guo, Zhili; Zhang, Liangxiao; Zhang, Yingying; Chen, Yinying; Nan, Jingyi; Zhao, Buchang; Xiao, Hongbin; Wang, Zhong; Wang, Yongyan

    2015-01-01

    The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke. PMID:26621314

  16. Assessment of the effects of dobutamine on myocardial blood flow and oxidative metabolism in normal human subjects using nitrogen-13 ammonia and carbon-11 acetate.

    PubMed

    Krivokapich, J; Huang, S C; Schelbert, H R

    1993-06-01

    The dual purposes of this study with positron emission tomography were to measure the effects of dobutamine on myocardial blood flow and oxidative metabolism, and to compare carbon-11 (C-11) acetate versus nitrogen-13 (N-13) ammonia in quantitating flow in normal subjects. Flow was quantitated with N-13 ammonia at rest and at peak dobutamine infusion (40 micrograms/kg/min) in 21 subjects. In 11 subjects, oxidative metabolism was also estimated at rest and peak dobutamine infusion using the clearance rate of C-11 acetate, k mono (min-1). A 2-compartment kinetic model was applied to the early phase of the C-11 acetate data to estimate flow. The rest and peak dobutamine rate-pressure products were 7,318 +/- 1,102 and 19,937 +/- 3,964 beats/min/mm Hg, respectively, and correlated well (r = 0.77) with rest and peak dobutamine flows of 0.77 +/- 0.14 and 2.25 ml/min/g determined using N-13 ammonia as a flow tracer. Rest and dobutamine flows estimated with C-11 acetate were highly correlated with those determined with N-13 ammonia (r = 0.92). k mono increased from 0.05 +/- 0.01 to 0.18 +/- 0.02 min-1, and correlated highly with the increase in flows (r = 0.91) and rate-pressure products (r = 0.94). Thus, the increase in cardiac demand associated with dobutamine is highly correlated with an increase in supply and oxidative metabolism. C-11 acetate is a unique tracer that can be used to image both flow and metabolism simultaneously. PMID:8498380

  17. Metabolic syndrome-related hepatocellular carcinoma treated by volumetric modulated arc therapy.

    PubMed

    Klein, J; Dawson, L A; Tran, T H; Adeyi, O; Purdie, T; Sherman, M; Brade, A

    2014-04-01

    Hepatocellular carcinoma (hcc) is a leading cause of cancer mortality, and its incidence is increasing in developed countries. Risk factors include cirrhosis from viral hepatitis or alcohol abuse. Metabolic syndrome is a newly recognized, but important, risk factor that is likely contributing to the increased incidence of hcc. Surgery is the therapy of choice for hcc, but local therapies are often contraindicated, usually because of advanced disease or comorbid conditions such as cardiac disease (which is associated with metabolic syndrome). Current radiation therapy techniques such as stereotactic body radiotherapy allow for treatment plans that highly conform to the target and provide excellent sparing of normal structures. Radiation therapy is emerging as a viable option in patients not eligible for surgery or other locoregional therapies. Here, we report a case of a large hcc presenting in a patient with metabolic syndrome without significant alcohol history or biochemical liver dysfunction. The patient was not a candidate for locoregional therapies because of cardiac and renal comorbidities typical of patients experiencing the long-term sequelae of metabolic syndrome. Treatment using an arc-based volumetric-modulated arc therapy technique allowed for the highest dose of radiation to be delivered to the tumour while the peripheral radiation dose was minimized. A complete local response was confirmed by computed tomography imaging 21 months after treatment completion. PMID:24764717

  18. Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

    PubMed Central

    Sobrevia, Luis; Salsoso, Rocío; Fuenzalida, Bárbara; Barros, Eric; Toledo, Lilian; Silva, Luis; Pizarro, Carolina; Subiabre, Mario; Villalobos, Roberto; Araos, Joaquín; Toledo, Fernando; González, Marcelo; Gutiérrez, Jaime; Farías, Marcelo; Chiarello, Delia I.; Pardo, Fabián; Leiva, Andrea

    2016-01-01

    Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies. PMID:27065887

  19. Synergistic effects between catalase inhibitors and modulators of nitric oxide metabolism on tumor cell apoptosis.

    PubMed

    Scheit, Katrin; Bauer, Georg

    2014-10-01

    Inhibitors of catalase (such as ascorbate, methyldopa, salicylic acid and neutralizing antibodies) synergize with modulators of nitric oxide (NO) metabolism (such as arginine, arginase inhibitor, NO synthase-inducing interferons and NO dioxygenase inhibitors) in the singlet oxygen-mediated inactivation of tumor cell protective catalase. This is followed by reactive oxygen species (ROS)-dependent apoptosis induction. TGF-beta, NADPH oxidase-1, NO synthase, dual oxidase-1 and caspase-9 are characterized as essential catalysts in this process. The FAS receptor and caspase-8 are required for amplification of ROS signaling triggered by individual compounds, but are dispensable when the synergistic effect is established. Our findings explain the antitumor effects of catalase inhibitors and of compounds that target NO metabolism, as well as their synergy. These data may have an impact on epidemiological studies related to secondary plant compounds and open new perspectives for the establishment of novel antitumor drugs and for the improvement of established chemotherapeutics. PMID:25275027

  20. Vitamin D Receptor Activation Protects Against Myocardial Reperfusion Injury Through Inhibition of Apoptosis and Modulation of Autophagy

    PubMed Central

    Yao, Tianbao; Ying, Xiaoying; Zhao, Yichao; Yuan, Ancai; He, Qing; Tong, Huan; Ding, Song; Liu, Junling; Peng, Xu; Gao, Erhe

    2015-01-01

    Abstract Aims: To determine the roles of vitamin D receptor (VDR) in ischemia/reperfusion-induced myocardial injury and to investigate the underlying mechanisms involved. Results: The endogenous VDR expression was detected in the mouse heart, and myocardial ischemia/reperfusion (MI/R) upregulated VDR expression. Activation of VDR by natural and synthetic agonists reduced myocardial infarct size and improved cardiac function. Mechanistically, VDR activation inhibited endoplasmic reticulum (ER) stress (determined by the reduction of CCAAT/enhancer-binding protein homologous protein expression and caspase-12 activation), attenuated mitochondrial impairment (determined by the decrease of mitochondrial cytochrome c release and caspase-9 activation), and reduced cardiomyocyte apoptosis. Furthermore, VDR activation significantly inhibited MI/R-induced autophagy dysfunction (determined by the inhibition of Beclin 1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, p62 protein abundance, and the restoration of autophagy flux). Moreover, VDR activation inhibited MI/R-induced oxidative stress through a metallothionein-dependent mechanism. The cardioprotective effects of VDR agonists mentioned earlier were impaired in the setting of cardiac-specific VDR silencing. In contrast, adenovirus-mediated cardiac VDR overexpression decreased myocardial infarct size and improved cardiac function through attenuating oxidative stress, and inhibiting apoptosis and autophagy dysfunction. Innovation and Conclusion: Our data demonstrate that VDR is a novel endogenous self-defensive and cardioprotective receptor against MI/R injury, via mechanisms (at least in part) reducing oxidative stress, and inhibiting apoptosis and autophagy dysfunction-mediated cell death. Antioxid. Redox Signal. 22, 633–650. PMID:25365634

  1. Murine Gut Microbiota Is Defined by Host Genetics and Modulates Variation of Metabolic Traits

    PubMed Central

    Lu, Lu; Williams, Evan G.; Brewer, Simon; Andreux, Pénélope A.; Bastiaansen, John W. M.; Wang, Xusheng; Kachman, Stephen D.; Auwerx, Johan; Williams, Robert W.; Benson, Andrew K.; Peterson, Daniel A.; Ciobanu, Daniel C.

    2012-01-01

    The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes–the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation. PMID:22723961

  2. Effect of SO/sub 2/ on light modulation of plant metabolism. Progress report

    SciTech Connect

    Anderson, L.E.

    1985-01-01

    This progress report briefly notes conclusions of work done on SO/sub 2/ effect on light modulation of plant metabolism. Conclusions include: effect of light activation on kinetic parameters of fructosebisphosphatase - for this enzyme K/sub m/ decreases and V/sub max/ increases as a result of light activation; and the effect of sulfite and arsenite on light activation in 2 Pisum cultivars - the differences in sensitivity to SO/sub 2/ is directly reflected in differences in a thylakoid bound factor (LEM) to SO/sub 2/.

  3. Modulation of fatty acid metabolism is involved in the alleviation of isoproterenol-induced rat heart failure by fenofibrate.

    PubMed

    Li, Ping; Luo, Shike; Pan, Chunji; Cheng, Xiaoshu

    2015-12-01

    Heart failure is a disease predominantly caused by an energy metabolic disorder in cardiomyocytes. The present study investigated the inhibitory effects of fenofibrate (FF) on isoproterenol (ISO)‑induced hear failure in rats, and examined the underlying mechanisms. The rats were divided into CON, ISO (HF model), FF and FF+ISO (HF animals pretreated with FF) groups. The cardiac structure and function of the rats were assessed, and contents of free fatty acids and glucose metabolic products were determined. In addition, myocardial cells were isolated from neonatal rats and used in vitro to investigate the mechanisms by which FF relieves heart failure. Western blot analysis was performed to quantify the expression levels of peroxisome proliferator‑activated receptor (PPAR)α and uncoupling protein 2 (UCP2). FF effectively alleviated the ISO‑induced cardiac structural damage, functional decline, and fatty acid and carbohydrate metabolic abnormalities. Compared with the ISO group, the serum levels of brain natriuretic peptide (BNP), free fatty acids, lactic acid and pyruvic acid were decreased in the FF animals. In the cultured myocardial cells, lactic acid and pyruvic acid contents were lower in the supernatants obtained from the FF animals, with lower levels of mitochondrial ROS production and cell necrosis, compared with the ISO group, whereas PPARα upregulation and UCP2 downregulation occurred in the FF+ISO group. The results demonstrated that FF efficiently alleviated heart failure in the ISO‑induced rat model, possibly via promoting fatty acid oxidation. PMID:26497978

  4. Dietary, Metabolic, and Potentially Environmental Modulation of the Lysine Acetylation Machinery

    PubMed Central

    Kim, Go-Woon; Gocevski, Goran; Wu, Chao-Jung; Yang, Xiang-Jiao

    2010-01-01

    Healthy lifestyles and environment produce a good state of health. A number of scientific studies support the notion that external stimuli regulate an individual's epigenomic profile. Epigenetic changes play a key role in defining gene expression patterns under both normal and pathological conditions. As a major posttranslational modification, lysine (K) acetylation has received much attention, owing largely to its significant effects on chromatin dynamics and other cellular processes across species. Lysine acetyltransferases and deacetylases, two opposing families of enzymes governing K-acetylation, have been intimately linked to cancer and other diseases. These enzymes have been pursued by vigorous efforts for therapeutic development in the past 15 years or so. Interestingly, certain dietary components have been found to modulate acetylation levels in vivo. Here we review dietary, metabolic, and environmental modulators of the K-acetylation machinery and discuss how they may be of potential value in the context of disease prevention. PMID:20976254

  5. Effects of metabolic and myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic neuropathy in type 2 diabetes mellitus: A prospective study in Japanese patients*

    PubMed Central

    Komori, Hiromi

    2005-01-01

    Background: In diabetic patients, cardiac autonomic neuropathy is an important factor affecting prognosis. Whether this condition in diabetic patients is caused directly by neurovisceral metabolic disorder and/or indirectly by micro circulation remains to be clarified. Objective: The aim of this study was to determine whether cardiac sympathetic nerve dysfunction can be detected using adenosine triphosphate (ATP) testing, while also investigating the effects of metabolic and/or myocardial microcirculatory abnormalities on the pathogenesis of cardiac autonomic nerve dysfunction in patients with type 2 diabetes mellitus (DM-2) in Japan. Methods: This prospective study was performed at the Division of Diabetology Department of Internal Medicine, Toho University, Ohashi Hospital, Tokyo, Japan. Patients aged ≥ 18 years with DM-2 with no abnormalities on electrocardiography (ECG) or echocardiography were enrolled. An ATP thallium (Tl)-201 myocardial scintigraphy test (ATP test) and iodine (I)-123 metaiodobenzylguanidine (MIBG) scintigraphy were performed. ATP was administered by continuous IV infusion over 6 minutes at 0.16 mg/kg · min. Five minutes after the ATP infusion was started, T1-201 111 MBq IV was administered. Single-photon emission computed tomography (SPECT) imaging was begun immediately after the end of ATP infusion and was completed 3 hours after stress to show washout from stress to rest. I-123 MIBG 111 MBq IV was administered. A planar image from the front side and a SPECT image (early phase) was obtained 15 to 30 minutes later. After 3 hours, a planar image from the front side and a SPECT image (late phase) were obtained to show washout from stress to rest. The mean TI washout rate (ATP-WR) and heart-to-mediastinum (H/M) ratio in the late-phase scintigraphic images and the washout rate of MIBG (MIBG-WR) in the left ventricle was determined. The correlations of these measurements with the mean values of glycosylated hemoglobin (HbA1c) and fasting

  6. Modulation of phosphoinositide metabolism in aortic smooth muscle cells by allylamine

    SciTech Connect

    Cox, L.R.; Murphy, S.K.; Ramos, K. )

    1990-08-01

    Aortic smooth muscle cells (SMC) modulate from a contractile to a proliferative phenotype upon subchronic exposure to allylamine. The present studies were designed to determine if this phenotypic modulation is associated with alterations in the metabolism of membrane phosphoinositides. 32P incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA) was lower by 31, 35, and 22%, respectively, in SMC from allylamine-treated animals relative to controls. In contrast, incorporation of (3H)myoinositol into inositol phosphates did not differ in allylamine cells relative to control cells. Exposure to dibutyryl (db) cAMP (0.2 mM) and theophylline (0.1 mM) reduced 32P incorporation into PIP and PIP2 in SMC from both experimental groups. Under these conditions, a decrease in (3H)myoinositol incorporation into inositol 1-phosphate was only observed in allylamine cells. The effects of db cAMP and theophylline in allylamine and control SMC correlated with a marked decrease in cellular proliferation. These results suggest that alterations in phosphoinositide synthesis and/or degradation contribute to the enhanced proliferation of SMC induced by allylamine. To further examine this concept, the effects of agents which modulate protein kinase C (PKC) activity were evaluated. Sphingosine (125-500 ng/ml), a PKC inhibitor, decreased SMC proliferation in allylamine, but not control cells. 12-O-Tetradecanoylphorbol-13-acetate (1-100 ng/ml), a PKC agonist, stimulated proliferation in control cells, but inhibited proliferation in cells from allylamine-treated animals. We conclude that allylamine-induced phenotypic modulation of SMC is associated with alterations in phosphoinositide metabolism.

  7. Metabolic phenotype modulation by caloric restriction in a lifelong dog study.

    PubMed

    Richards, Selena E; Wang, Yulan; Claus, Sandrine P; Lawler, Dennis; Kochhar, Sunil; Holmes, Elaine; Nicholson, Jeremy K

    2013-07-01

    profiles enabled an unbiased evaluation of the metabolic markers modulated by a lifetime of caloric restriction and showed differences in the metabolic phenotype of aging due to caloric restriction, which contributes to longevity studies in caloric-restricted animals. Furthermore, OPLS-DA provided a framework such that significant metabolites relating to life extension could be differentiated and integrated with aging processes. PMID:23713866

  8. Age-related changes in retinoic, docosahexaenoic and arachidonic acid modulation in nuclear lipid metabolism.

    PubMed

    Gaveglio, Virginia L; Pascual, Ana C; Giusto, Norma M; Pasquaré, Susana J

    2016-08-15

    The aim of this work was to study how age-related changes could modify several enzymatic activities that regulate lipid mediator levels in nuclei from rat cerebellum and how these changes are modulated by all-trans retinoic acid (RA), docosahexaenoic acid (DHA) and arachidonic acid (AA). The higher phosphatidate phosphohydrolase activity and lower diacylglycerol lipase (DAGL) activity observed in aged animals compared with adults could augment diacylglycerol (DAG) availability in the former. Additionally, monoacylglycerol (MAG) availability could be high due to an increase in lysophosphatidate phosphohydrolase (LPAPase) activity and a decrease in monocylglycerol lipase activity. Interestingly, RA, DHA and AA were observed to modulate these enzymatic activities and this modulation was found to change in aged rats. In adult nuclei, whereas RA led to high DAG and MAG production through inhibition of their hydrolytic enzymes, DHA and AA promoted high MAG production by LPAPase and DAGL stimulation. In contrast, in aged nuclei RA caused high MAG generation whereas DHA and AA diminished it through LPAPase activity modulation. These results demonstrate that aging promotes a different nuclear lipid metabolism as well as a different type of non-genomic regulation by RA, DHA and AA, which could be involved in nuclear signaling events. PMID:27355428

  9. 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

  10. Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia

    PubMed Central

    2014-01-01

    Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential. PMID:24438487

  11. Metabolic Reprogramming of Host Cells by Virulent Francisella tularensis for Optimal Replication and Modulation of Inflammation.

    PubMed

    Wyatt, Elliott V; Diaz, Karina; Griffin, Amanda J; Rasmussen, Jed A; Crane, Deborah D; Jones, Bradley D; Bosio, Catharine M

    2016-05-15

    A shift in macrophage metabolism from oxidative phosphorylation to aerobic glycolysis is a requirement for activation to effectively combat invading pathogens. Francisella tularensis is a facultative intracellular bacterium that causes an acute, fatal disease called tularemia. Its primary mechanism of virulence is its ability to evade and suppress inflammatory responses while replicating in the cytosol of macrophages. The means by which F. tularensis modulates macrophage activation are not fully elucidated. In this study, we demonstrate that virulent F. tularensis impairs production of inflammatory cytokines in primary macrophages by preventing their shift to aerobic glycolysis, as evidenced by the downregulation of hypoxia inducible factor 1α and failure to upregulate pfkfb3 We also show that Francisella capsule is required for this process. In addition to modulating inflammatory responses, inhibition of glycolysis in host cells is also required for early replication of virulent Francisella Taken together, our data demonstrate that metabolic reprogramming of host cells by F. tularensis is a key component of both inhibition of host defense mechanisms and replication of the bacterium. PMID:27029588

  12. Salmonella Modulates Metabolism During Growth under Conditions that Induce Expression of Virulence Genes

    SciTech Connect

    Kim, Young-Mo; Schmidt, Brian; Kidwai, Afshan S.; Jones, Marcus B.; Deatherage, Brooke L.; Brewer, Heather M.; Mitchell, Hugh D.; Palsson, Bernhard O.; McDermott, Jason E.; Heffron, Fred; Smith, Richard D.; Peterson, Scott N.; Ansong, Charles; Hyduke, Daniel R.; Metz, Thomas O.; Adkins, Joshua N.

    2013-04-05

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Excitingly, we observed possible sequestration of metabolites recently suggested to have immune modulating roles. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Model-guided analysis suggested that alterations in metabolism prioritized other activities necessary for pathogenesis instead, such as lipopolysaccharide biosynthesis.

  13. Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism

    PubMed Central

    Moyer, Adam L.; Wagner, Kathryn R.

    2015-01-01

    Background The transforming growth factor β (TGF-β) signaling pathways modulate skeletal muscle growth, regeneration, and cellular metabolism. Several recent gene expression studies have shown that inhibition of myostatin and TGF-β1 signaling consistently leads to a significant reduction in expression of Mss51, also named Zmynd17. The function of mammalian Mss51 is unknown although a putative homolog in yeast is a mitochondrial translational activator. Objective The objective of this work was to characterize mammalian Mss51. Methods Quantitative RT-PCR and immunoblot of subcellular fractionation were used to determine expression patterns and localization of Mss51. The CRISPR/Cas9 system was used to reduce expression of Mss51 in C2C12 myoblasts and the function of Mss51 was evaluated in assays of proliferation, differentiation and cellular metabolism. Results Mss51 was predominantly expressed in skeletal muscle and in those muscles dominated by fast-twitch fibers. In vitro, its expression was upregulated upon differentiation of C2C12 myoblasts into myotubes. Expression of Mss51 was modulated in response to altered TGF-β family signaling. In human muscle, Mss51 localized to the mitochondria. Its genetic disruption resulted in increased levels of cellular ATP, β-oxidation, glycolysis, and oxidative phosphorylation. Conclusions Mss51 is a novel, skeletal muscle-specific gene and a key target of myostatin and TGF-β1 signaling. Unlike myostatin, TGF-β1 and IGF-1, Mss51 does not regulate myoblast proliferation or differentiation. Rather, Mss51 appears to be one of the effectors of these growth factors on metabolic processes including fatty acid oxidation, glycolysis and oxidative phosphorylation. PMID:26634192

  14. Controlled delivery of a metabolic modulator promotes regulatory T cells and restrains autoimmunity.

    PubMed

    Gammon, Joshua M; Tostanoski, Lisa H; Adapa, Arjun R; Chiu, Yu-Chieh; Jewell, Christopher M

    2015-07-28

    Autoimmune disorders occur when the immune system abnormally recognizes and attacks self-molecules. Dendritic cells (DCs) play a powerful role in initiating adaptive immune response, and are therefore a recent target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a small molecule glutamate receptor enhancer, alters how DCs metabolize glutamate, skewing cytokine secretion to bias T cell function. These effects provide protection in mouse models of multiple sclerosis (MS) by polarizing T cells away from inflammatory TH17 cells and toward regulatory T cells (TREG) when mice receive daily systemic injections of PHCCC. However, frequent, continued treatment is required to generate and maintain therapeutic benefits. Thus, the use of PHCCC is limited by poor solubility, the need for frequent dosing, and cell toxicity. We hypothesized that controlled release of PHCCC from degradable nanoparticles (NPs) might address these challenges by altering DC function to maintain efficacy with reduced treatment frequency and toxicity. This idea could serve as a new strategy for harnessing biomaterials to polarize immune function through controlled delivery of metabolic modulators. PHCCC was readily encapsulated in nanoparticles, with controlled release of 89% of drug into media over three days. Culture of primary DCs or DC and T cell co-cultures with PHCCC NPs reduced DC activation and secretion of pro-inflammatory cytokines, while shifting T cells away from TH17 and toward TREG phenotypes. Importantly, PHCCC delivered to cells in NPs was 36-fold less toxic compared with soluble PHCCC. Treatment of mice with PHCCC NPs every three days delayed disease onset and decreased disease severity compared with mice treated with soluble drug at the same dose and frequency. These results highlight the potential to promote tolerance through controlled delivery of metabolic modulators that alter DC signaling to polarize T cells, and suggest future

  15. Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand.

    PubMed

    Hauton, David; Al-Shammari, Abdullah; Gaffney, Eamonn A; Egginton, Stuart

    2015-01-01

    Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14C-labelled glucose and 3H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve

  16. Maternal Hypoxia Decreases Capillary Supply and Increases Metabolic Inefficiency Leading to Divergence in Myocardial Oxygen Supply and Demand

    PubMed Central

    Hauton, David; Al-Shammari, Abdullah; Gaffney, Eamonn A.; Egginton, Stuart

    2015-01-01

    Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14C-labelled glucose and 3H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve

  17. Maladaptive Modulations of NLRP3 Inflammasome and Cardioprotective Pathways Are Involved in Diet-Induced Exacerbation of Myocardial Ischemia/Reperfusion Injury in Mice

    PubMed Central

    Penna, Claudia; Nigro, Debora; Chiazza, Fausto; Fracasso, Veronica; Tullio, Francesca; Aragno, Manuela

    2016-01-01

    Excessive fatty acids and sugars intake is known to affect the development of cardiovascular diseases, including myocardial infarction. However, the underlying mechanisms are ill defined. Here we investigated the balance between prosurvival and detrimental pathways within the heart of C57Bl/6 male mice fed a standard diet (SD) or a high-fat high-fructose diet (HFHF) for 12 weeks and exposed to cardiac ex vivo ischemia/reperfusion (IR) injury. Dietary manipulation evokes a maladaptive response in heart mice, as demonstrated by the shift of myosin heavy chain isoform content from α to β, the increased expression of the Nlrp3 inflammasome and markers of oxidative metabolism, and the downregulation of the hypoxia inducible factor- (HIF-)2α and members of the Reperfusion Injury Salvage Kinases (RISK) pathway. When exposed to IR, HFHF mice hearts showed greater infarct size and lactic dehydrogenase release in comparison with SD mice. These effects were associated with an exacerbated overexpression of Nlrp3 inflammasome, resulting in marked caspase-1 activation and a compromised activation of the cardioprotective RISK/HIF-2α pathways. The common mechanisms of damage here reported lead to a better understanding of the cross-talk among prosurvival and detrimental pathways leading to the development of cardiovascular disorders associated with metabolic diseases. PMID:26788246

  18. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

    PubMed Central

    Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

    2015-01-01

    The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

  19. Combined Angiotensin Receptor Modulation in the Management of Cardio-Metabolic Disorders.

    PubMed

    Paulis, Ludovit; Foulquier, Sébastien; Namsolleck, Pawel; Recarti, Chiara; Steckelings, Ulrike Muscha; Unger, Thomas

    2016-01-01

    Cardiovascular and metabolic disorders, such as hypertension, insulin resistance, dyslipidemia or obesity are linked with chronic low-grade inflammation and dysregulation of the renin-angiotensin system (RAS). Consequently, RAS inhibition by ACE inhibitors or angiotensin AT1 receptor (AT1R) blockers is the evidence-based standard for cardiovascular risk reduction in high-risk patients, including diabetics with albuminuria. In addition, RAS inhibition reduces the new onset of diabetes mellitus. Yet, the high and increasing prevalence of metabolic disorders, and the high residual risk even in properly treated patients, calls for additional means of pharmacological intervention. In the past decade, the stimulation of the angiotensin AT2 receptor (AT2R) has been shown to reduce inflammation, improve cardiac and vascular remodeling, enhance insulin sensitivity and increase adiponectin production. Therefore, a concept of dual AT1R/AT2R modulation emerges as a putative means for risk reduction in cardio-metabolic diseases. The approach employing simultaneous RAS blockade (AT1R) and RAS stimulation (AT2R) is distinct from previous attempts of double intervention in the RAS by dual blockade. Dual blockade abolishes the AT1R-linked RAS almost completely with subsequent risk of hypotension and hypotension-related events, i.e. syncope or renal dysfunction. Such complications might be especially prominent in patients with renal impairment or patients with isolated systolic hypertension and normal-to-low diastolic blood pressure values. In contrast to dual RAS blockade, the add-on of AT2R stimulation does not exert significant blood pressure effects, but it may complement and enhance the anti-inflammatory and antifibrotic/de-stiffening effects of the AT1R blockade and improve the metabolic profile. Further studies will have to investigate these putative effects in particular for settings in which blood pressure reduction is not primarily desired. PMID:26631237

  20. Utility of Glycated Hemoglobin for Assessment of Glucose Metabolism in Patients With ST-Segment Elevation Myocardial Infarction.

    PubMed

    Aggarwal, Bhuvnesh; Shah, Gautam K; Randhawa, Mandeep; Ellis, Stephen G; Lincoff, Abraham Michael; Menon, Venu

    2016-03-01

    Glycated hemoglobin (HbA1c) is an approved and widely used laboratory investigation for diagnosis of diabetes that is not affected by acute changes in blood glucose. Our aim was to analyze the extent to which routine HbA1c measurements diagnose unknown diabetes mellitus (DM) in patients presenting with ST-segment elevation myocardial infarction (STEMI). We also compared outcomes in patients with newly diagnosed DM, previously established DM and those without DM. Consecutive patients undergoing PCI for STEMI from January 2005 to December 2012 were included and routinely performed admission HbA1c was used to identify patients with previously undiagnosed DM (HbA1c ≥6.5 and no history of DM or DM therapy) and pre-DM (HbA1c 5.7% to 6.4%). Overall 1,686 consecutive patients underwent primary percutaneous coronary intervention for STEMI during the study period and follow-up data were available for 1,566 patients (90%). A quarter of the patients (24%, n = 405) had history of DM, 7% (n = 118) had previously undiagnosed DM, and 38.7% (n = 652) had pre-DM. Mortality was comparable in patients with known DM and newly diagnosed DM both in-hospital (11.1% vs 11.9%, p = 0.87) and at 3-year follow-up (27.3% and 24%). Patients with DM, including those who were newly diagnosed, had higher mortality at 3 years (26.5%) compared to those with pre-DM (12.1%) or no dysglycemia (11.2%, p <0.01). In conclusion, a substantial number of patients with STEMI have previously undiagnosed DM (7%). These patients have similar in-hospital and long-term mortality as those with known DM, and outcomes are inferior to patients without dysglycemia. PMID:26768673

  1. Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together.

    PubMed

    Wang, Xianwei; Ding, Zufeng; Yang, Fen; Dai, Yao; Chen, Peng; Theus, Sue; Singh, Sharda; Budhiraja, Madhu; Mehta, Jawahar L

    2016-08-01

    Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia. PMID:27129181

  2. Building a Better Infarct: Modulation of Collagen Cross-linking to Increase Infarct Stiffness and Reduce Left Ventricular Dilation post-Myocardial Infarction

    PubMed Central

    Voorhees, Andrew P.; DeLeon-Pennell, Kristine Y.; Ma, Yonggang; Halade, Ganesh V.; Yabluchanskiy, Andriy; Iyer, Rugmani Padmanabhan; Flynn, Elizabeth; Cates, Courtney A.; Lindsey, Merry L.; Han, Hai-Chao

    2015-01-01

    Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood. The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n=88) and MMP-9 null (MMP-9−/−; n=92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n=42). At day 7 post-MI, WT LVs displayed a 3-fold increase in end-diastolic volume, while MMP-9−/− showed only a 2-fold increase (p<0.05). Biaxial mechanical testing revealed that MMP-9−/− infarcts were stiffer than WT infarcts, as indicated by a 1.3-fold reduction in predicted in vivo circumferential stretch (p<0.05). Paradoxically, MMP-9−/− infarcts had a 1.8-fold reduction in collagen deposition (p<0.05). This apparent contradiction was explained by a 3.1-fold increase in lysyl oxidase (p<0.05) in MMP-9−/− infarcts, indicating that MMP-9 deletion increased collagen cross-linking activity. Furthermore, MMP-9 deletion led to a 3.0-fold increase in bone morphogenetic protein-1, the metalloproteinase that cleaves pro-collagen and pro-lysyl oxidase (p<0.05) and reduced fibronectin fragmentation by 49% (p<0.05) to enhance lysyl oxidase activity. We conclude that MMP-9 deletion increases infarct stiffness and prevents LV dilation by reducing collagen degradation and facilitating collagen assembly and cross-linking through preservation of the fibronectin network and activation of lysyl oxidase. PMID:26080361

  3. Modulation of xenobiotic-metabolizing enzymes by ethanolic neem leaf extract during hamster buccal pouch carcinogenesis.

    PubMed

    Subapriya, R; Velmurugan, B; Nagini, S

    2005-06-01

    Chemoprevention by medicinal plants is a promising approach for controlling cancer. There is substantial evidence to indicate that chemopreventive agents exert their anticarcinogenic effects by modulation of phase I and phase II xenobiotic-metabolizing enzymes. Therefore, we examined the chemopreventive potential of ethanolic neem leaf extract (ENLE) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Hamsters were divided into four groups of six animals each. The right buccal pouches of animals in Group I were painted with 0.5 per cent DMBA in liquid paraffin three times per week. Animals in Group 2 painted with DMBA as in group 1, received in addition, intragastric administration of ENLE at a concentration of 200 mg/kg bw three times per week on days alternate to DMBA application. Group 3 was given ENLE alone. Animals in Group 4 served as controls. All animals were killed after an experimental period of 14 weeks. Five out of six hamsters painted with DMBA alone developed squamous cell carcinomas in the buccal pouch. The HBP tumours showed an increase in phase I carcinogen activation (cytochrome P450 and b5) and phase II detoxification enzyme (glutathione-S-transferase, DT-diaphorase and NADPH-diaphorase) activities. In the liver of tumour-bearing animals, enhanced cytochrome P450 and b5 levels were accompanied by a decrease in phase II detoxification enzyme activities. Administration of ENLE effectively suppressed DMBA-induced HBP tumours, decreased cytochrome P450 and b5 levels, and enhanced phase II enzyme activities in the pouch and liver. Our results suggest that the modulation of DMBA metabolism is a possible mechanism for the chemopreventive effects of ethanolic neem leaf extract. PMID:16110755

  4. Dichotomous Metabolism of Enterococcus faecalis Induced by Hematin Starvation Modulates Colonic Gene Expression

    PubMed Central

    Allen, Toby D.; Moore, Danny R.; Wang, Xingmin; Casu, Viviana; May, Randal; Lerner, Megan R.; Houchen, Courtney; Brackett, Daniel J.; Huycke, Mark M.

    2009-01-01

    Summary Enterococcus faecalis is an intestinal commensal that cannot synthesize porphyrins and only expresses a functional respiratory chain when provided exogenous hematin. In the absence of hematin, E. faecalis reverts to fermentative metabolism and produces extracellular superoxide that can damage epithelial cell DNA. The acute response of the colonic mucosa to hematin-starved E. faecalis was identified by gene array. E. faecalis was inoculated into murine colons using a surgical ligation model that preserved tissue architecture and homeostasis. The mucosa was exposed to hematin-starved E. faecalis and compared to a control consisting of the same strain grown with hematin. At 1 hour post-inoculation six mucosal genes were differentially regulated and this increased to 42 genes at 6 hours. At 6 hours a highly significant biological interaction network was identified with functions that included NF-κB signaling, apoptosis, and cell cycle regulation. Colon biopsies showed no histological abnormalities by hematoxylin and eosin staining. Immunohistochemical staining, however, detected NF-κB activation in tissue macrophages using antibodies to the nuclear localization sequence for p65 and the F4/80 marker for murine macrophages. Similarly, hematin-starved E. faecalis strongly activated NF-κB in murine macrophages in vitro. Furthermore, primary and transformed colonic epithelial cells activated the G2/M checkpoint in vitro following exposure to hematin-starved E. faecalis. Modulation of this cell cycle checkpoint was due to extracellular superoxide produced as a result of the respiratory block in hematin-starved E. faecalis. These results demonstrate that the uniquely dichotomous metabolism of E. faecalis can significantly modulate gene expression in the colonic mucosa for pathways associated with inflammation, apoptosis, and cell cycle regulation. PMID:18809545

  5. Sneaker Male Squid Produce Long-lived Spermatozoa by Modulating Their Energy Metabolism.

    PubMed

    Hirohashi, Noritaka; Tamura-Nakano, Miwa; Nakaya, Fumio; Iida, Tomohiro; Iwata, Yoko

    2016-09-01

    Spermatozoa released by males should remain viable until fertilization. Hence, sperm longevity is governed by intrinsic and environmental factors in accordance with the male mating strategy. However, whether intraspecific variation of insemination modes can impact sperm longevity remains to be elucidated. In the squid Heterololigo bleekeri, male dimorphism (consort and sneaker) is linked to two discontinuous insemination modes that differ in place and time. Notably, only sneaker male spermatozoa inseminated long before egg spawning can be stored in the seminal receptacle. We found that sneaker spermatozoa exhibited greater persistence in fertilization competence and flagellar motility than consort ones because of a larger amount of flagellar glycogen. Sneaker spermatozoa also showed higher capacities in glucose uptake and lactate efflux. Lactic acidosis was considered to stabilize CO2-triggered self-clustering of sneaker spermatozoa, thus establishing hypoxia-induced metabolic changes and sperm survival. These results, together with comparative omics analyses, suggest that postcopulatory reproductive contexts define sperm longevity by modulating the inherent energy levels and metabolic pathways. PMID:27385589

  6. Low Concentrations of Nitric Oxide Modulate Streptococcus pneumoniae Biofilm Metabolism and Antibiotic Tolerance.

    PubMed

    Allan, Raymond N; Morgan, Samantha; Brito-Mutunayagam, Sanjita; Skipp, Paul; Feelisch, Martin; Hayes, Stephen M; Hellier, William; Clarke, Stuart C; Stoodley, Paul; Burgess, Andrea; Ismail-Koch, Hasnaa; Salib, Rami J; Webb, Jeremy S; Faust, Saul N; Hall-Stoodley, Luanne

    2016-04-01

    Streptococcus pneumoniaeis one of the key pathogens responsible for otitis media (OM), the most common infection in children and the largest cause of childhood antibiotic prescription. Novel therapeutic strategies that reduce the overall antibiotic consumption due to OM are required because, although widespread pneumococcal conjugate immunization has controlled invasive pneumococcal disease, overall OM incidence has not decreased. Biofilm formation represents an important phenotype contributing to the antibiotic tolerance and persistence ofS. pneumoniaein chronic or recurrent OM. We investigated the treatment of pneumococcal biofilms with nitric oxide (NO), an endogenous signaling molecule and therapeutic agent that has been demonstrated to trigger biofilm dispersal in other bacterial species. We hypothesized that addition of low concentrations of NO to pneumococcal biofilms would improve antibiotic efficacy and that higher concentrations exert direct antibacterial effects. Unlike in many other bacterial species, low concentrations of NO did not result inS. pneumoniaebiofilm dispersal. Instead, treatment of bothin vitrobiofilms andex vivoadenoid tissue samples (a reservoir forS. pneumoniaebiofilms) with low concentrations of NO enhanced pneumococcal killing when combined with amoxicillin-clavulanic acid, an antibiotic commonly used to treat chronic OM. Quantitative proteomic analysis using iTRAQ (isobaric tag for relative and absolute quantitation) identified 13 proteins that were differentially expressed following low-concentration NO treatment, 85% of which function in metabolism or translation. Treatment with low-concentration NO, therefore, appears to modulate pneumococcal metabolism and may represent a novel therapeutic approach to reduce antibiotic tolerance in pneumococcal biofilms. PMID:26856845

  7. Low level light in combination with metabolic modulators for effective therapy

    NASA Astrophysics Data System (ADS)

    Dong, Tingting; Zhang, Qi; Hamblin, Michael R.; Wu, Mei X.

    2015-03-01

    Vascular damage occurs frequently at the injured brain causing hypoxia and is associated with poor outcomes in the clinics. We found high levels of glycolysis, reduced ATP generation, and increased formation of reactive oxygen species (ROS) and apoptosis in neurons under hypoxia. Strikingly, these adverse events were reversed significantly by noninvasive exposure of injured brain to low-level light (LLL). LLL illumination sustained the mitochondrial membrane potential, constrained cytochrome C leakage in hypoxic cells, and protected them from apoptosis, underscoring a unique property of LLL. The effect of LLL was further bolstered by combination with metabolic substrates such as pyruvate or lactate both in vivo and in vitro. The combinational treatment retained memory and learning activities of injured mice to a normal level, whereas those treated with LLL or pyruvate alone, or sham light displayed partial or severe deficiency in these cognitive functions. In accordance with well-protected learning and memory function, the hippocampal region primarily responsible for learning and memory was completely protected by a combination of LLL and pyruvate, in marked contrast to the severe loss of hippocampal tissue due to secondary damage in control mice. These data clearly suggest that energy metabolic modulators can additively or synergistically enhance the therapeutic effect of LLL in energy-producing insufficient tissues like injured brain. Keywords:

  8. Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming.

    PubMed

    Tveit, Alexander Tøsdal; Urich, Tim; Frenzel, Peter; Svenning, Mette Marianne

    2015-05-12

    Arctic permafrost soils store large amounts of soil organic carbon (SOC) that could be released into the atmosphere as methane (CH4) in a future warmer climate. How warming affects the complex microbial network decomposing SOC is not understood. We studied CH4 production of Arctic peat soil microbiota in anoxic microcosms over a temperature gradient from 1 to 30 °C, combining metatranscriptomic, metagenomic, and targeted metabolic profiling. The CH4 production rate at 4 °C was 25% of that at 25 °C and increased rapidly with temperature, driven by fast adaptations of microbial community structure, metabolic network of SOC decomposition, and trophic interactions. Below 7 °C, syntrophic propionate oxidation was the rate-limiting step for CH4 production; above this threshold temperature, polysaccharide hydrolysis became rate limiting. This change was associated with a shift within the functional guild for syntrophic propionate oxidation, with Firmicutes being replaced by Bacteroidetes. Correspondingly, there was a shift from the formate- and H2-using Methanobacteriales to Methanomicrobiales and from the acetotrophic Methanosarcinaceae to Methanosaetaceae. Methanogenesis from methylamines, probably stemming from degradation of bacterial cells, became more important with increasing temperature and corresponded with an increased relative abundance of predatory protists of the phylum Cercozoa. We concluded that Arctic peat microbiota responds rapidly to increased temperatures by modulating metabolic and trophic interactions so that CH4 is always highly produced: The microbial community adapts through taxonomic shifts, and cascade effects of substrate availability cause replacement of functional guilds and functional changes within taxa. PMID:25918393

  9. Genistein reduced insulin resistance index through modulating lipid metabolism in ovariectomized rats.

    PubMed

    Choi, Joo Sun; Koh, In-Uk; Song, Jihyun

    2012-11-01

    Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of β-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance. PMID:23176795

  10. Metabolic and trophic interactions modulate methane production by Arctic peat microbiota in response to warming

    PubMed Central

    Tveit, Alexander Tøsdal; Urich, Tim; Frenzel, Peter; Svenning, Mette Marianne

    2015-01-01

    Arctic permafrost soils store large amounts of soil organic carbon (SOC) that could be released into the atmosphere as methane (CH4) in a future warmer climate. How warming affects the complex microbial network decomposing SOC is not understood. We studied CH4 production of Arctic peat soil microbiota in anoxic microcosms over a temperature gradient from 1 to 30 °C, combining metatranscriptomic, metagenomic, and targeted metabolic profiling. The CH4 production rate at 4 °C was 25% of that at 25 °C and increased rapidly with temperature, driven by fast adaptations of microbial community structure, metabolic network of SOC decomposition, and trophic interactions. Below 7 °C, syntrophic propionate oxidation was the rate-limiting step for CH4 production; above this threshold temperature, polysaccharide hydrolysis became rate limiting. This change was associated with a shift within the functional guild for syntrophic propionate oxidation, with Firmicutes being replaced by Bacteroidetes. Correspondingly, there was a shift from the formate- and H2-using Methanobacteriales to Methanomicrobiales and from the acetotrophic Methanosarcinaceae to Methanosaetaceae. Methanogenesis from methylamines, probably stemming from degradation of bacterial cells, became more important with increasing temperature and corresponded with an increased relative abundance of predatory protists of the phylum Cercozoa. We concluded that Arctic peat microbiota responds rapidly to increased temperatures by modulating metabolic and trophic interactions so that CH4 is always highly produced: The microbial community adapts through taxonomic shifts, and cascade effects of substrate availability cause replacement of functional guilds and functional changes within taxa. PMID:25918393

  11. Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is associated with a chronic low grade inflammation characterized by high level of pro-inflammatory cytokines and mediators implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been shown to modulate immune-based pathol...

  12. Sevoflurane postconditioning reduces myocardial reperfusion injury in rat isolated hearts via activation of PI3K/Akt signaling and modulation of Bcl-2 family proteins*

    PubMed Central

    Yu, Li-na; Yu, Jing; Zhang, Feng-jiang; Yang, Mei-juan; Ding, Ting-ting; Wang, Jun-kuan; He, Wei; Fang, Tao; Chen, Gang; Yan, Min

    2010-01-01

    Sevoflurane postconditioning reduces myocardial infarct size. The objective of this study was to examine the role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in anesthetic postconditioning and to determine whether PI3K/Akt signaling modulates the expression of pro- and antiapoptotic proteins in sevoflurane postconditioning. Isolated and perfused rat hearts were prepared first, and then randomly assigned to the following groups: Sham-operation (Sham), ischemia/reperfusion (Con), sevoflurane postconditioning (SPC), Sham plus 100 nmol/L wortmannin (Sham+Wort), Con+Wort, SPC+Wort, and Con+dimethylsulphoxide (DMSO). Sevoflurane postconditioning was induced by administration of sevoflurane (2.5%, v/v) for 10 min from the onset of reperfusion. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), maximum increase in rate of LVDP (+dP/dt), maximum decrease in rate of LVDP (−dP/dt), heart rate (HR), and coronary flow (CF) were measured at baseline, R30 min (30 min of reperfusion), R60 min, R90 min, and R120 min. Creatine kinase (CK) and lactate dehydrogenase (LDH) were measured after 5 min and 10 min reperfusion. Infarct size was determined by triphenyltetrazolium chloride staining at the end of reperfusion. Total Akt and phosphorylated Akt (phospho-Akt), Bax, Bcl-2, Bad, and phospho-Bad were determined by Western blot analysis. Analysis of variance (ANOVA) and Student-Newman-Keuls’ test were used to investigate the significance of differences between groups. The LVDP, ±dP/dt, and CF were higher and LVEDP was lower in the SPC group than in the Con group at all points of reperfusion (P<0.05). The SPC group had significantly reduced CK and LDH release and decreased infarct size compared with the Con group [(22.9±8)% vs. (42.4±9.4)%, respectively; P<0.05]. The SPC group also had increased the expression of phosphor-Akt, Bcl-2, and phospho-Bad, and decreased the expression of Bax. Wortmannin abolished the

  13. Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle.

    PubMed

    Supriya, Rashmi; Tam, Bjorn T; Pei, Xiao M; Lai, Christopher W; Chan, Lawrence W; Yung, Benjamin Y; Siu, Parco M

    2016-01-01

    Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at -80°C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser(636∕639), and pAktSer(473)) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer(79). Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle. PMID:27512375

  14. Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle

    PubMed Central

    Supriya, Rashmi; Tam, Bjorn T.; Pei, Xiao M.; Lai, Christopher W.; Chan, Lawrence W.; Yung, Benjamin Y.; Siu, Parco M.

    2016-01-01

    Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at −80°C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser636∕639, and pAktSer473) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer79. Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle. PMID:27512375

  15. Cell Walls of Saccharomyces cerevisiae Differentially Modulated Innate Immunity and Glucose Metabolism during Late Systemic Inflammation

    PubMed Central

    Baurhoo, Bushansingh; Ferket, Peter; Ashwell, Chris M.; de Oliviera, Jean; Zhao, Xin

    2012-01-01

    Background Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS) from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. Methods and Principal Findings Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic) on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK) and liver glycolysis (ENO2), and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS) down-regulation and ATP citrate lyase (ACLY) and malic enzyme (ME) up-regulations. However, MOS host's lower energy

  16. The low density lipoprotein receptor modulates the effects of hypogonadism on diet-induced obesity and related metabolic perturbations

    PubMed Central

    Constantinou, Caterina; Mpatsoulis, Diogenis; Natsos, Anastasios; Petropoulou, Peristera-Ioanna; Zvintzou, Evangelia; Traish, Abdulmaged M.; Voshol, Peter J.; Karagiannides, Iordanes; Kypreos, Kyriakos E.

    2014-01-01

    Here, we investigated how LDL receptor deficiency (Ldlr−/−) modulates the effects of testosterone on obesity and related metabolic dysfunctions. Though sham-operated Ldlr−/− mice fed Western-type diet for 12 weeks became obese and showed disturbed plasma glucose metabolism and plasma cholesterol and TG profiles, castrated mice were resistant to diet-induced obesity and had improved glucose metabolism and reduced plasma TG levels, despite a further deterioration in their plasma cholesterol profile. The effect of hypogonadism on diet-induced weight gain of Ldlr−/− mice was independent of ApoE and Lrp1. Indirect calorimetry analysis indicated that hypogonadism in Ldlr−/− mice was associated with increased metabolic rate. Indeed, mitochondrial cytochrome c and uncoupling protein 1 expression were elevated, primarily in white adipose tissue, confirming increased mitochondrial metabolic activity due to thermogenesis. Testosterone replacement in castrated Ldlr−/− mice for a period of 8 weeks promoted diet-induced obesity, indicating a direct role of testosterone in the observed phenotype. Treatment of sham-operated Ldlr−/− mice with the aromatase inhibitor exemestane for 8 weeks showed that the obesity of castrated Ldlr−/− mice is independent of estrogens. Overall, our data reveal a novel role of Ldlr as functional modulator of metabolic alterations associated with hypogonadism. PMID:24837748

  17. Modulation of fructokinase activity of potato (Solanum tuberosum) results in substantial shifts in tuber metabolism.

    PubMed

    Davies, Howard V; Shepherd, Louise V T; Burrell, Michael M; Carrari, Fernando; Urbanczyk-Wochniak, Ewa; Leisse, Andrea; Hancock, Robert D; Taylor, Mark; Viola, Roberto; Ross, Heather; McRae, Diane; Willmitzer, Lothar; Fernie, Alisdair R

    2005-07-01

    Potato plants (Solanum tuberosum L. cvs Desiree and Record) transformed with sense and antisense constructs of a cDNA encoding the potato fructokinase StFK1 exhibited altered transcription of this gene, altered amount of protein and altered enzyme activities. Measurement of the maximal catalytic activity of fructokinase revealed a 2-fold variation in leaf (from 90 to 180% of wild type activity) and either a 10- or 30-fold variation in tuber (from 10 or 30% to 300% in Record and Desiree, respectively) activity. The comparative effect of the antisense construct in leaf and tuber tissue suggests that this isoform is only a minor contributor to the total fructokinase activity in the leaf but the predominant isoform in the tuber. Antisense inhibition of the fructokinase resulted in a reduced tuber yield; however, its overexpression had no impact on this parameter. The modulation of fructokinase activity had few, consistent effects on carbohydrate levels, with the exception of a general increase in glucose content in the antisense lines, suggesting that this enzyme is not important for the control of starch synthesis. However, when metabolic fluxes were estimated, it became apparent that the transgenic lines display a marked shift in metabolism, with the rate of redistribution of radiolabel to sucrose markedly affected by the activity of fructokinase. These data suggest an important role for fructokinase, acting in concert with sucrose synthase, in maintaining a balance between sucrose synthesis and degradation by a mechanism independent of that controlled by the hexose phosphate-mediated activation of sucrose phosphate synthase. PMID:15890680

  18. Antimutagenic potential and modulation of carcinogen-metabolizing enzymes by ginger essential oil.

    PubMed

    Jeena, Kottarapat; Liju, Vijayasteltar B; Viswanathan, Ramanath; Kuttan, Ramadasan

    2014-06-01

    Essential oil extracted from ginger (GEO) was evaluated for its mutagenicity to Salmonella typhimurium TA 98, TA 100, TA 102, and TA 1535 strains with and without microsomal activation. GEO was found to be non-mutagenic up to a concentration of 3 mg/plate. It was also assessed for antimutagenic potential against direct acting mutagens such as sodium azide, 4-nitro-o-phenylenediamine, N-methyl-N'-nitro-N-nitrosoguanidine, tobacco extract, and 2-acetamidoflourene, which needs microsomal activation. GEO significantly inhibited (p < 0.001) the mutagenicity induced by these agents in a concentration-dependent manner. The effect of GEO to modulate the action of phase I carcinogen-metabolizing enzymes was investigated by studying its effect on various isoforms of microsomal cytochrome P450 enzymes. Significant inhibition of CYP1A1, CYP1A2, and CYP2B1/2, aniline hydroxylase (an indicator of CYP2E1 activity), and aminopyrine-N-demethylase (indicator of CYP1A, 2A, 2B, 2D, and 3A activity) was shown by GEO both in vitro and in vivo. GEO gave an IC50 value of 30, 57.5, and 40 µg for CYP1A1, CYP1A2, and CYP2B1/2, respectively, 55 µg for aniline hydroxylase, and 37.5 µg for aminopyrene-N-demethylase. GEO also significantly increased the levels of phase II carcinogen-metabolizing enzymes uridine 5'-diphospho-glucuronyl transferase and glutathione-S-transferase in vivo indicating the use of GEO as an antimutagen and as a potential chemopreventive agent. PMID:24023002

  19. The metabolic modulator trimetazidine triggers autophagy and counteracts stress-induced atrophy in skeletal muscle myotubes.

    PubMed

    Ferraro, Elisabetta; Giammarioli, Anna Maria; Caldarola, Sara; Lista, Pasquale; Feraco, Alessandra; Tinari, Antonella; Salvatore, Anna Maria; Malorni, Walter; Berghella, Libera; Rosano, Giuseppe

    2013-10-01

    It has recently been demonstrated that trimetazidine (TMZ), an anti-ischemic antianginal agent, is also able to improve exercise performance in patients with peripheral arterial disease. TMZ is a metabolic modulator, and the mechanisms underlying its cytoprotective anti-ischemic activity could be ascribed, at least in cardiomyocytes, to optimization of metabolism. However, regarding the cytoprotection exerted by TMZ on skeletal muscle and allowing the improvement of exercise performance, no information is yet available. In the present study, we investigated in detail the protective effects of this drug on in vitro skeletal muscle models of atrophy. Experiments carried out with murine C2C12 myotubes treated with TMZ revealed that this drug could efficiently counteract the cytopathic effects induced by the proinflammatory cytokine tumor necrosis factor-α and by the withdrawal of growth factors. Indeed, TMZ significantly counteracted the reduction in myotube size induced by these treatments. TMZ also increased myosin heavy chain expression and induced hypertrophy in C2C12 myotubes, both effects strongly suggesting a role of TMZ in counteracting atrophy in vitro. In particular, we found that TMZ was able to activate the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin 2 pathway and to reduce the stress-induced transcriptional upregulation of atrogin-1, muscle ring finger protein 1, and myostatin, all of which are key molecules involved in muscle wasting. Moreover, this is the first demonstration that TMZ induces autophagy, a key mechanism involved in muscle mass regulation. On the basis of these results, it can be hypothesized that the improvement in exercise performance previously observed in patients could be ascribed to a cytoprotective mechanism exerted by TMZ on skeletal muscle integrity. PMID:23953053

  20. Modulation of fatty acid and bile acid metabolism by PPARα protects against alcoholic liver disease

    PubMed Central

    Li, Heng-Hong; Tyburski, John B.; Wang, Yiwen; Strawn, Steve; Moon, Bo-Hyun; Kallakury, Bhaskar V. S.; Gonzalez, Frank J.; Fornace, Albert J.

    2014-01-01

    Background Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor α (PPARα)-null mice developed more pronounced hepatic changes than wild type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of ALD in Ppara-null model and in humans, and the fact that PPARα expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD. Methods In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARα activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in wild-type mice. Results The results showed that in the presence of PPARα, three major metabolic pathways in mitochondria, namely the fatty acid β-oxidation, the tricarboxylic acid cycle (TCA) and the electron transfer chain, were induced in response to two-month alcohol feeding, while these responses were greatly reduced in the absence of PPARα. In line with the transcriptional modulations of these metabolic pathways, lipidomic profiling showed consistent accumulation of triglycerides in Ppara-null mice, a robust increase of hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes exclusively in alcohol-fed Ppara-null mice. Conclusions These observations indicate that PPARα plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment of ALD. PMID:24773203

  1. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine

    PubMed Central

    Pin, Fabrizio; Gorini, Stefania; Pontecorvo, Laura; Ferri, Alberto; Mollace, Vincenzo; Costelli, Paola; Rosano, Giuseppe

    2016-01-01

    Abstract Background The loss of muscle mass (sarcopenia) and the associated reduced muscle strength are key limiting factors for elderly people's quality of life. Improving muscle performance does not necessarily correlate with increasing muscle mass. In fact, particularly in the elderly, the main explanation for muscle weakness is a reduction of muscle quality rather than a loss of muscle mass, and the main goal to be achieved is to increase muscle strength. The effectiveness of Trimetazidine (TMZ) in preventing muscle functional impairment during ageing was assessed in our laboratory. Methods Aged mice received TMZ or vehicle for 12 consecutive days. Muscle function was evaluated at the end of the treatment by a grip test as well as by an inverted screen test at 0, 5, 7 and 12 days of TMZ treatment. After sacrifice, muscles were stored for myofiber cross‐sectional area assessment and myosin heavy chain expression evaluation by western blotting. Results Chronic TMZ treatment does not affect the mass of both gastrocnemius and tibialis anterior muscles, while it significantly increases muscle strength. Indeed, both latency to fall and grip force are markedly enhanced in TMZ‐treated versus untreated mice. In addition, TMZ administration results in higher expression of slow myosin heavy chain isoform and increased number of small‐sized myofibers. Conclusions We report here some data showing that the modulation of skeletal muscle metabolism by TMZ increases muscle strength in aged mice. Reprogramming metabolism might therefore be a strategy worth to be further investigated in view of improving muscle performance in the elderly. PMID:27239426

  2. Dengue Virus NS1 Protein Modulates Cellular Energy Metabolism by Increasing Glyceraldehyde-3-Phosphate Dehydrogenase Activity

    PubMed Central

    Allonso, Diego; Andrade, Iamara S.; Conde, Jonas N.; Coelho, Diego R.; Rocha, Daniele C. P.; da Silva, Manuela L.; Ventura, Gustavo T.

    2015-01-01

    ABSTRACT Dengue is one of the main public health concerns worldwide. Recent estimates indicate that over 390 million people are infected annually with the dengue virus (DENV), resulting in thousands of deaths. Among the DENV nonstructural proteins, the NS1 protein is the only one whose function during replication is still unknown. NS1 is a 46- to 55-kDa glycoprotein commonly found as both a membrane-associated homodimer and a soluble hexameric barrel-shaped lipoprotein. Despite its role in the pathogenic process, NS1 is essential for proper RNA accumulation and virus production. In the present study, we identified that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with intracellular NS1. Molecular docking revealed that this interaction occurs through the hydrophobic protrusion of NS1 and the hydrophobic residues located at the opposite side of the catalytic site. Moreover, addition of purified recombinant NS1 enhanced the glycolytic activity of GAPDH in vitro. Interestingly, we observed that DENV infection promoted the relocalization of GAPDH to the perinuclear region, where NS1 is commonly found. Both DENV infection and expression of NS1 itself resulted in increased GAPDH activity. Our findings indicate that the NS1 protein acts to increase glycolytic flux and, consequently, energy production, which is consistent with the recent finding that DENV induces and requires glycolysis for proper replication. This is the first report to propose that NS1 is an important modulator of cellular energy metabolism. The data presented here provide new insights that may be useful for further drug design and the development of alternative antiviral therapies against DENV. IMPORTANCE Dengue represents a serious public health problem worldwide and is caused by infection with dengue virus (DENV). Estimates indicate that half of the global population is at risk of infection, with almost 400 million cases occurring per year. The NS1 glycoprotein is found in both the

  3. Myocardial Noncompaction Presenting With Myocardial Bridge

    PubMed Central

    Shen, Yuechun; Li, Xinchun; Lu, Dongfeng; Xiao, Aiyi; Li, Jun

    2015-01-01

    Abstract Myocardial noncompaction, namly isolated noncompaction of the left ventricular myocardium (NVM), is a rare congenital disease. It can be either seen in the absence of other cardiac anomalies, or associated with other congenital cardiac defects, mostly stenotic lesions of the left ventricular outflow tract. A myocardial bridge (MB) is thought being associated with coronary heart disease, such as coronary spasm, arrhythmia, and so on. The significance of MB in association with other congenital cardiac conditions is unknown. We report a novel case who was presented NVM and MB. A 34-year-old man complained of chest prickling-like pain and dizzy for 1 year. His blood pressure was 110/70 mm Hg. Echocardiograph revealed increased trabeculations below the level of papillary muscle of left ventricle (LV); deep intertrabecular recesses in the endocardial wall of LV particularly in apex free wall; and LV ejection fraction of 57%. A coronary computerized tomography scan showed that part, 38.9 cm, of left descending artery tunnel was surrounding by cardiac muscles rather than resting on top of the myocardium. The therapeutics interventions included lifestyle cares, agents of anti-ischemia and improvement myocardial cell metabolism. The patient was followed up for 2.6 years, and his general condition was stable. This case indicates that NVM can be developed with MB, and the complete diagnosis of NVM and MB should be made by different image studies. PMID:26356695

  4. Concerted modulation of alanine and glutamate metabolism in young Medicago truncatula seedlings under hypoxic stress

    PubMed Central

    Limami, Anis M.; Glévarec, Gaëlle; Ricoult, Claudie; Cliquet, Jean-Bernard; Planchet, Elisabeth

    2008-01-01

    The modulation of primary nitrogen metabolism by hypoxic stress was studied in young Medicago truncatula seedlings. Hypoxic seedlings were characterized by the up-regulation of glutamate dehydrogenase 1 (GDH1) and mitochondrial alanine aminotransferase (mAlaAT), and down-regulation of glutamine synthetase 1b (GS1b), NADH-glutamate synthase (NADH-GOGAT), glutamate dehydrogenase 3 (GDH3), and isocitrate dehydrogenase (ICDH) gene expression. Hypoxic stress severely inhibited GS activity and stimulated NADH-GOGAT activity. GDH activity was lower in hypoxic seedlings than in the control, however, under either normoxia or hypoxia, the in vivo activity was directed towards glutamate deamination. 15NH4 labelling showed for the first time that the adaptive reaction of the plant to hypoxia consisted of a concerted modulation of nitrogen flux through the pathways of both alanine and glutamate synthesis. In hypoxic seedlings, newly synthesized 15N-alanine increased and accumulated as the major amino acid, asparagine synthesis was inhibited, while 15N-glutamate was synthesized at a similar rate to that in the control. A discrepancy between the up-regulation of GDH1 expression and the down-regulation of GDH activity by hypoxic stress highlighted for the first time the complex regulation of this enzyme by hypoxia. Higher rates of glycolysis and ethanol fermentation are known to cause the fast depletion of sugar stores and carbon stress. It is proposed that the expression of GDH1 was stimulated by hypoxia-induced carbon stress, while the enzyme protein might be involved during post-hypoxic stress contributing to the regeneration of 2-oxoglutarate via the GDH shunt. PMID:18508812

  5. Thiamine modulates metabolism of the phenylpropanoid pathway leading to enhanced resistance to Plasmopara viticola in grapevine

    PubMed Central

    2013-01-01

    Background Previously, we have reported the ability of thiamine (vitamin B1) to induce resistance against Plasmopara viticola in a susceptible grapevine cv. Chardonnay. However, mechanisms underlying vitamins, especially, thiamine-induced disease resistance in grapevine are still largely unknown. Here, we assessed whether thiamine could modulate phenylpropanoid pathway-derived phytoalexins in grapevine plants, as well as, the role of such secondary metabolites in thiamine-induced resistance process to P. viticola. Results Our data show that thiamine treatment elicited the expression of phenylpropanoid pathway genes in grapevine plants. The expression of these genes correlated with an accumulation of stilbenes, phenolic compounds, flavonoids and lignin. Furthermore, the total anti-oxidant potential of thiamine-treaded plants was increased by 3.5-fold higher level as compared with untreated-control plants. Four phenolic compounds are responsible of 97% of the total anti-oxidant potential of thiamine-treated plants. Among these compounds, is the caftaric acid, belonging to the hydroxy-cinnamic acids family. This element contributed, by its own, by 20% of this total anti-oxidant potential. Epifluorescence microscopy analysis revealed a concomitant presence of unbranched-altered P. viticola mycelia and stilbenes production in the leaf mesophyll of thiamine-treated inoculated plants, suggesting that stilbenes are an important component of thiamine-induced resistance in grapevine. Conclusion This work is the first to show the role of thiamine, as a vitamin, in the modulation of grapevine plant secondary metabolism contributing to an enhanced resistance to P. viticola, the most destructive fungal disease in vineyards. PMID:23442597

  6. Pretreatment with black tea polyphenols modulates xenobiotic-metabolizing enzymes in an experimental oral carcinogenesis model

    PubMed Central

    Letchoumy, P. Vidjaya; Mohan, K. V. P Chandra; Stegeman, J. J.; Gelboin, H. V.; Hara, Y.; Nagini, S.

    2014-01-01

    Objective To evaluate the chemopreventive potential of the black tea polyphenols Polyphenon-B and BTF-35 during the preinitiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Design Hamsters were divided into 6 groups. Groups 2 and 3 animals received diet containing Polyphenon-B and BTF-35 respectively, four weeks before carcinogen administration when they were 6 weeks of age and continued until the final exposure to carcinogen. At 10 weeks of age, animals in groups 1, 2 and 3 were painted with 0.5% DMBA 3 times a week for 14 weeks. Groups 4 and 5 animals were given Polyphenon-B and BTF-35 alone respectively as in groups 2 and 3. Animals in group 6 served as control. All the animals were sacrificed after an experimental period of 18 weeks. Phase I and phase II xenobiotic-metabolizing enzymes and 8-hydroxy deoxyguanosine (8-OH dG) in the buccal pouch and liver were used as biomarkers of chemoprevention. Results Hamsters painted with DMBA showed increased expression of 8-OH-dG and enhanced activities of phase I (CYP450; total as well as CYP1A1, 1A2 and 2B isoforms and cytochrome b5) and phase II (GST and quinone reductase) xenobiotic-metabolizing enzymes with increased immunohistochemical expression of CYP1A1, and CYP1B1 isoforms in the buccal pouch. This was accompanied by increased phase I and decreased phase II enzyme activities in the liver. Administration of Polyphenon-B and BTF-35 significantly decreased tumour incidence, oxidative DNA damage, phase I enzyme activities as well as expression of CYP1A1 and CYP1B1 isoforms, while enhancing phase II enzyme activities in the buccal pouch and liver. Conclusion Our results provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. Furthermore, the greater efficacy of BTF-35 in chemoprevention of HBP carcinomas via inhibition of oxidative DNA damage and modulation of xenobiotic-metabolizing enzymes may have a major impact in human oral

  7. Pretreatment with black tea polyphenols modulates xenobiotic-metabolizing enzymes in an experimental oral carcinogenesis model.

    PubMed

    Vidjaya Letchoumy, P; Chandra Mohan, K V P; Stegeman, J J; Gelboin, H V; Hara, Y; Nagini, S

    2008-01-01

    The objective of this study was to evaluate the chemopreventive potential of the black tea polyphenols Polyphenon-B and BTF-35 during the preinitiation phase of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Hamsters were divided into six groups. Animals in groups 2 and 3 received diet containing Polyphenon-B and BTF-35, respectively, 4 weeks before carcinogen administration when they were 6 weeks of age and continued until the final exposure to carcinogen. At 10 weeks of age, animals in groups 1, 2, and 3 were painted with 0.5% DMBA three times a week for 14 weeks. Animals in groups 4 and 5 were given Polyphenon-B and BTF-35 alone, respectively, as in groups 2 and 3. Animals in group 6 served as control. All the animals were sacrificed after an experimental period of 18 weeks. Phase I and phase II xenobiotic-metabolizing enzymes and 8-hydroxy-deoxyguanosine (8-OH-dG) in the buccal pouch and liver were used as biomarkers of chemoprevention. Hamsters painted with DMBA showed increased expression of 8-OH-dG and enhanced activities of phase I (CYP450; total as well as CYP1A1, 1A2, and 2B isoforms and cytochrome b5) and phase II (GST and quinone reductase) xenobiotic-metabolizing enzymes with increased immunohistochemical expression of CYP1A1, and CYP1B1 isoforms in the buccal pouch. This was accompanied by increased phase I and decreased phase II enzyme activities in the liver. Administration of Polyphenon-B and BTF-35 significantly decreased tumor incidence, oxidative DNA damage, phase I enzyme activities as well as expression of CYP1A1 and CYP1B1 isoforms, while enhancing phase II enzyme activities in the buccal pouch and liver. Our results provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. Furthermore, the greater efficacy of BTF-35 in chemoprevention of HBP carcinomas via inhibition of oxidative DNA damage and modulation of xenobiotic-metabolizing enzymes may have a major impact in

  8. Myocardial Bridge

    MedlinePlus

    ... artery. See also on this site: Ask a Texas Heart Institute Doctor: Search "myocardial bridge" Updated August ... comments. Terms of Use and Privacy Policy © Copyright Texas Heart Institute All rights reserved.

  9. Transmammary modulation of xenobiotic metabolizing enzymes in liver of mouse pups by mace (Myristica fragrans Houtt.).

    PubMed

    Chhabra, S K; Rao, A R

    1994-05-01

    The present study examines the possible transfer of the active principle(s) of mace (aril of the plant Myristica fragrans) through the transmammary route and its ability to modulate hepatic xenobiotic metabolizing enzymes in the F1 progeny of mice. An aqueous suspension of mace at the dose levels of 0.025 or 0.1 g/animal/day was administered by oral gavage to dams from day 1 of lactation and continued daily for 14 or 21 days. Dams receiving mace treatment and their F1 pups showed significantly elevated hepatic sulfhydryl content, glutathione S-transferase and glutathione reductase activities and cytochrome b5 content. Hepatic cytochrome P450 content decreased in dams (P < 0.05) receiving the lower mace dose for 21 days and the F1 pups (P < 0.001), but increased in dams receiving the higher dose for both time periods (P < 0.001) and the lower dose for 14 days (P < 0.05). Only the 14-day-old pups of dams receiving either mace dose showed significantly elevated (P < 0.001) levels of hepatic glutathione peroxidase. PMID:7934086

  10. Galanin peptide family as a modulating target for contribution to metabolic syndrome.

    PubMed

    Fang, Penghua; Yu, Mei; Shi, Mingyi; Zhang, Zhenwen; Sui, Yumei; Guo, Lili; Bo, Ping

    2012-10-01

    Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease. PMID:22909974