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Review

Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy

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Pages 755-766 | Received 12 Aug 2015, Accepted 26 Nov 2015, Published online: 08 Jan 2016

References

  • Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. New England J Med. 2002;347(5):305–313.
  • Alpert MA. Obesity Cardiomyopathy: Pathophysiology and Evolution of the Clinical Syndrome. Am J Med Sci. 2001;321(4):225–236.
  • Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. New England J Med. 2006;355(3):251–259.
  • Rayner J, Neubauer S, Rider O. The paradox of obesity cardiomyopathy and the potential for weight loss as a therapy. Obes Rev. 2015;16(8):679–690.
  • Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev. 2008;88(2):389–419.
  • Neubauer S. The failing heart—an engine out of fuel. New England J Med. 2007;356(11):1140–1151.
  • Caetano-Anollés G, Kim HS, Mittenthal JE. The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture. Proc Natl Acad Sci. 2007;104(22):9358–9363.
  • Lopaschuk GD, Folmes CD, Stanley WC. Cardiac energy metabolism in obesity. Circ Res. 2007;101(4):335–347.
  • Wu P, Sato J, Zhao Y, et al. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem. J. 1998;329:197–201.
  • Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med. 2000;10(6):238–245.
  • Varga T, Czimmerer Z, Nagy L. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta (BBA)-Mol Basis Dis. 2011;1812(8):1007–1022.
  • Jensen MD, Haymond MW, Rizza RA, et al. Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Investig. 1989;83(4):1168.
  • Vyska K, Machulla H, Stremmel W, et al. Regional myocardial free fatty acid extraction in normal and ischemic myocardium. Circulation. 1988;78(5):1218–1233.
  • Zhou Y-T, Grayburn P, Karim A, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci. 2000;97(4):1784–1789.
  • Keller HR, Dreyer C, Medin J, et al. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci. 1993;90(6):2160–2164.
  • Wende AR, Huss JM, Schaeffer PJ, et al. PGC-1α coactivates PDK4 gene expression via the orphan nuclear receptor ERRα: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol. 2005;25(24):10684–10694.
  • Kirchner H, Nylen C, Laber S, et al. Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass. Surg Obes Relat Dis. 2014;10(4):671–678.
  • Young ME, Guthrie PH, Razeghi P, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes. 2002;51(8):2587–2595.
  • Buchanan J, Mazumder PK, Hu P, et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology. 2005;146(12):5341–5349.
  • Kolter T, Uphues I, Eckel J. Molecular analysis of insulin resistance in isolated ventricular cardiomyocytes of obese Zucker rats. Am J Physiol-Endocrinol Metab. 1997;273(1):E59–E67.
  • Chatham JC, Seymour A-M L. Cardiac carbohydrate metabolism in Zucker diabetic fatty rats. Cardiovasc Res. 2002;55(1):104–112.
  • Peterson LR, Herrero P, Schechtman KB, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004;109(18):2191–2196.
  • Labbé SM, Grenier-Larouche T, Noll C, et al. Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes. 2012;61(11):2701–2710.
  • Rosa G, Rocco P, Manco M, et al. Reduced PDK4 expression associates with increased insulin sensitivity in postobese patients. Obes Res. 2003;11(2):176–182.
  • Viljanen AP, Karmi A, Borra R, et al. Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol. 2009;103(12):1721–1726.
  • Fenk S, Fischer M, Strack C, et al. Successful weight reduction improves left ventricular diastolic function and physical performance in severe obesity. Int Heart J. 2015;56(2):196–202.
  • Sankaralingam S, Alrob OA, Zhang L, et al. Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox. Diabetes. 2015;64(5):1643–1657.
  • Sidhu S, Gangasani A, Korotchkina LG, et al. Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice. Am J Physiol-Heart Circ Physiol. 2008;295(3):H946–H952.
  • Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109(1):121–130.
  • Chambers KT, Leone TC, Sambandam N, et al. Chronic inhibition of pyruvate dehydrogenase in heart triggers an adaptive metabolic response. J Biol Chem. 2011;286(13):11155–11162.
  • Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice. Am J Physiol-Endocrinol Metab. 2008;295(1):E46–E54.
  • Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(5):852–871.
  • Chokshi A, Drosatos K, Cheema FH, et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation. 2012;125(23):2844–2853.
  • Crewe C, Kinter M, Szweda LI. Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart. Plos One. 2013;8(10):e77280.
  • Crewe CL, Kinter M, Szweda L. Adaptation of the Heart to High-Dietary Fat: Rapid Inhibition Of Pyruvate Dehydrogenase. FASEB J. 2013;27(1):1192.24.
  • Scaglione R, Dichiara M, Indovina A, et al. Left ventricular diastolic and systolic function in normotensive obese subjects: influence of degree and duration of obesity. Eur Heart J. 1992;13(6):738–742.
  • Ritov VB, Menshikova EV, He J, et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes. 2005;54(1):8–14.
  • Neubauer S, Krahe T, Schindler R, et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered Cardiac High-Energy Phosphate Metab Heart Failure Circ. 1992;86(6):1810–1818.
  • Rider O, Francis J, Tyler D, et al. Effects of weight loss on myocardial energetics and diastolic function in obesity. Int J Cardiovasc Imaging. 2013;29(5):1043–1050.
  • Rider OJ, Francis JM, M K A, et al. Effects of catecholamine stress on diastolic function and myocardial energetics in obesity. Circulation. 2012;125(12):1511–1519.
  • Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, Leukotrienes and Essent Fatty Acids. 2004;70(3):309–319.
  • Mjøs OD, Kjekshus JK, Lekven J. Importance of free fatty acids as a determinant of myocardial oxygen consumption and myocardial ischemic injury during norepinephrine infusion in dogs. J Clin Investig. 1974;53(5):1290.
  • Das SR, Alexander KP, Chen AY, et al. Impact of body weight and extreme obesity on the presentation, treatment, and in-hospital outcomes of 50,149 patients with ST-segment elevation myocardial infarction: results from the NCDR (National Cardiovascular Data Registry). J Am Coll Cardiol. 2011;58(25):2642–2650.
  • McVeigh JJ, Lopaschuk GD. Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Physiol-Heart Circ Physiol. 1990;259(4):H1079–H1085.
  • Thakker GD, Frangogiannis NG, Bujak M, et al. Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction. Am J Physiol-Heart Circ Physiol. 2006;291(5):H2504–H2514.
  • Greer JJ, Ware DP, Lefer DJ. Myocardial infarction and heart failure in the db/db diabetic mouse. Am J Physiol-Heart Circ Physiol. 2006;290(1):H146–H153.
  • Maarman G, Marais E, Lochner A, et al. Effect of chronic CPT-1 inhibition on myocardial ischemia-reperfusion injury (I/R) in a model of diet-induced obesity. Cardiovasc Drugs Ther. 2012;26(3):205–216.
  • Malmberg K, Rydén L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26(1):57–65.
  • Selker HP, Udelson JE, Massaro JM, et al. One-year outcomes of out-of-hospital administration of intravenous glucose, insulin, and potassium (GIK) in patients with suspected acute coronary syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care] Trial). Am J Cardiol. 2014;113(10):1599–1605.
  • Phan TT, Frenneaux M. The pathophysiology of diastolic heart failure. F1000 Biol Rep. 2010;2:16. DOI:10.3410/B2-16.
  • Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res. 2004;95(2):135–145.
  • Tian R, Nascimben L, Ingwall JS, et al. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation. 1997;96(4):1313–1319.
  • Bers DM. Sarcoplasmic reticulum Ca uptake, content and release, in Excitation-contraction coupling and cardiac contractile force. Dordrecht: Springer; 2001. p. 161–202.
  • Kammermeier H. High energy phosphate of the myocardium: concentration versus free energy change, in Cardiac Energetics. Berlin: Springer; 1987. p. 31–36.
  • Boudina S, Sena S, Theobald H, et al. Mitochondrial Energetics in the Heart in Obesity-Related Diabetes Direct Evidence for Increased Uncoupled Respiration and Activation of Uncoupling Proteins. Diabetes. 2007;56(10):2457–2466.
  • Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. The Lancet. 2004;364(9447):1786–1788.
  • Boudina S, Han YH, Pei S, et al. UCP3 Regulates Cardiac Efficiency and Mitochondrial Coupling in High Fat–Fed Mice but Not in Leptin-Deficient Mice. Diabetes. 2012;61(12):3260–3269.
  • Essop MF, Razeghi P, McLeod C, et al. Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling. Biochem Biophys Res Commun. 2004;314(2):561–564.
  • Muoio DM. Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell. 2014;159(6):1253–1262.
  • Nabben M, van Bree BW, Lenaers E, et al. Lack of UCP3 does not affect skeletal muscle mitochondrial function under lipid-challenged conditions, but leads to sudden cardiac death. Basic Res Cardiol. 2014;109(6):1–12.
  • Sverdlov AL, Elezaby A, Behring JB, et al. High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II. J Mol Cell Cardiol. 2015;78:165–173.
  • Mjøs OD. Effect of free fatty acids on myocardial function and oxygen consumption in intact dogs. J Clin Investig. 1971;50(7):1386.
  • Carley AN, Taegtmeyer H, Lewandowski ED. Matrix Revisited Mechanisms Linking Energy Substrate Metabolism to the Function of the Heart. Circ Res. 2014;114(4):717–729.
  • Christoffersen C, Bollano E, Lindegaard ML, et al. Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology. 2003;144(8):3483–3490.
  • Chiu H-C, Kovacs A, Blanton RM, et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res. 2005;96(2):225–233.
  • Yang J, Sambandam N, Han X, et al. CD36 deficiency rescues lipotoxic cardiomyopathy. Circ Res. 2007;100(8):1208–1217.
  • Pulinilkunnil T, Kienesberger PC, Nagendran J, et al. Myocardial adipose triglyceride lipase overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy. Diabetes. 2013;62(5):1464–1477.
  • Banerjee R, Rial B, Holloway CJ, et al. Evidence of a Direct Effect of Myocardial Steatosis on LV Hypertrophy and Diastolic Dysfunction in Adult and Adolescent Obesity. JACC: Cardiovasc Imaging. 2015. doi:10.1016/j.jcmg.2014.12.019.
  • Stanley WC, Hernandez LA, Spires D, et al. Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. J Mol Cell Cardiol. 1996;28(5):905–914.
  • Wynn RM, Kato M, Chuang JL, et al. Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem. 2008;283(37):25305–25315.
  • Curry SH, Chu PI, Baumgartner TG, et al. Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate. Clin Pharmacol Ther. 1985;37(1):89–93.
  • Evans OB, Stacpoole PW. Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate. Biochem Pharmacol. 1982;31(7):1295–1300.
  • Stacpoole PW, Moore GW, Kornhauser DM. Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. New England J Med. 1978;298(10):526–530.
  • Le Page LM, Rider OJ, Lewis AJ, et al. Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study. Diabetes. 2015;64(8):2735–2743.
  • Nicholl TA, Lopaschuk GD, McNeill JH. Effects of free fatty acids and dichloroacetate on isolated working diabetic rat heart. Am J Physiol-Heart Circ Physiol. 1991;261(4):H1053–H1059.
  • Bersin RM, Wolfe C, Kwasman M, et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol. 1994;23(7):1617–1624.
  • Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS A randomized, controlled clinical trial. Neurology. 2006;66(3):324–330.
  • Shroads AL, Langaee T, Coats BS, et al. Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. J Clin Pharmacol. 2012;52(6):837–849.
  • Ferriero R, Manco G, Lamantea E, et al. Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci Transl Med. 2013;5(175):175ra31–175ra31.
  • Ferriero R, Iannuzzi C, Manco G, et al. Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate. J Inherit Metab Dis. 2015;38(5):895–904.
  • Tso S-C, Qi X, Gui W-J, et al. Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket. J Biol Chem. 2014;289(7):4432–4443.
  • Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86(5):580–588.
  • Allibardi S, Chierchia SL, Margonato V, et al. Effects of trimetazidine on metabolic and functional recovery of postischemic rat hearts. Cardiovasc Drugs Ther. 1998;12(6):543–549.
  • Fragasso G, Perseghin G, De Cobelli F, et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur Heart J. 2006;27(8):942–948.
  • Ussher JR, Fillmore N, Keung W, et al. Trimetazidine Therapy Prevents Obesity-Induced Cardiomyopathy in Mice. Can J Cardiol. 2014;30(8):940–944.
  • Ussher JR, Keung W, Fillmore N, et al. Treatment with the 3-Ketoacyl-CoA Thiolase Inhibitor Trimetazidine Does Not Exacerbate Whole-Body Insulin Resistance in Obese Mice. J Pharmacol Exp Ther. 2014;349(3):487–496.
  • Kuzmicic J, Parra V, Verdejo HE, et al. Trimetazidine prevents palmitate-induced mitochondrial fission and dysfunction in cultured cardiomyocytes. Biochem Pharmacol. 2014;91(3):323–336.
  • Holubarsch C, Rohrbach M, Karrasch M, et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin Sci. 2007;113:205–212.
  • Clarke B, Wyatt KM. McCormack J G Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. J Mol Cell Cardiol. 1996;28(2):341–350.
  • Maier L, Wachter R, Edelmann F, et al. Ranolazine for the treatment of diastolic heart failure in patients with preserved ejection fraction: results from the RALI-DHF study. J Am Coll Cardiol. 2012;59(13s1):E865–E865.
  • Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153–165.
  • Zhao T, Parikh P, Bhashyam S, et al. Direct effects of glucagon-like peptide-1 on myocardial contractility and glucose uptake in normal and postischemic isolated rat hearts. J Pharmacol Exp Ther. 2006;317(3):1106–1113.
  • Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110(8):955–961.
  • Lewis AJ, Dodd MS, Sourdon J, et al. Hyperpolarized 13C and 31P magnetic resonance spectroscopy identify pyruvate dehydrogenase as a therapeutic target in obesity cardiomyopathy. J Cardiovasc Magn Reson. 2015;17(Suppl 1):O16.
  • Liu L, Trent CM, Fang X, et al. Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure. J Biol Chem. 2014;289(43):29881–29891.
  • Aroor AR, Sowers JR, Bender SB, et al. Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. Endocrinology. 2013;154(7):2501–2513.
  • Bostick B, Habibi J, Ma L, et al. Dipeptidyl peptidase inhibition prevents diastolic dysfunction and reduces myocardial fibrosis in a mouse model of Western diet induced obesity. Metabolism. 2014;63(8):1000–1011.
  • Noyan-Ashraf MH, Shikatani EA, Schuiki I, et al. A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity. Circulation. 2013;127(1):74–85.
  • Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Investig. 1998;101(3):515.
  • Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. New England J Med. 2015;373(3):232–242.

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