Autophagy, myocardial protection, and the metabolic syndrome

Journal of Cardiovascular Pharmacology

Volumn 60, Issue 2, 2012, Pages 125-132

  Giricz, Zoltan ^a   Mentzer, Robert M ^a,b,c   Gottlieb, Roberta A ^a  

^a SAN DIEGO STATE UNIVERSITY   (United States)

^b Cardiovascular Research Institute   (United States)

^c WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

autophagy; cardioprotection; metabolic syndrome; myocardial ischemia and reperfusion

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; AUTOPHAGY PROTEIN 5; AUTOPHAGY PROTEIN 7; BECLIN 1; BIGUANIDE DERIVATIVE; CHLORAMPHENICOL; CYCLIC GMP DERIVATIVE; GLYCOGEN SYNTHASE KINASE 3BETA; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INSULIN; LEPTIN; MAMMALIAN TARGET OF RAPAMYCIN; MEMBRANE PROTEIN; METFORMIN; PARKIN; PIOGLITAZONE; PROTEIN KINASE B; RAPAMYCIN; RECOMBINANT LEPTIN; RESVERATROL; ROSIGLITAZONE; SIMVASTATIN; STREPTOZOCIN; UNCLASSIFIED DRUG;

APOPTOSIS; AUTOPHAGY; CELL DEATH; CORONARY ARTERY OBSTRUCTION; DIABETES MELLITUS; DISEASE ASSOCIATION; DISEASE SEVERITY; DRUG EFFICACY; DRUG INHIBITION; DRUG POTENCY; DYSLIPIDEMIA; ENERGY CONSUMPTION; EXERCISE; FOOD INTAKE; GENE OVEREXPRESSION; HEART; HEART DISEASE; HEART FAILURE; HEART INFARCTION; HEART INFARCTION SIZE; HEART MUSCLE; HEART MUSCLE ISCHEMIA; HEART PROTECTION; HEART STRESS; HEART VENTRICLE HYPERTROPHY; HEART VENTRICLE REMODELING; HEAT TOLERANCE; HUMAN; HYPERGLYCEMIA; HYPERTENSION; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; ISCHEMIC PRECONDITIONING; LIGHT CHAIN; METABOLIC SYNDROME X; MITOPHAGY; NONHUMAN; OBESITY; OXIDATIVE STRESS; PRIORITY JOURNAL; PROGNOSIS; PROTEIN INDUCTION; PROTEIN PHOSPHORYLATION; RECEPTOR DOWN REGULATION; RECEPTOR UPREGULATION; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; AUTOPHAGY; ENERGY METABOLISM; HUMANS; ISCHEMIC PRECONDITIONING, MYOCARDIAL; METABOLIC SYNDROME X; MYOCARDIAL REPERFUSION INJURY; MYOCARDIUM; STRESS, PHYSIOLOGICAL; VENTRICULAR REMODELING;

EID: 84865610149     PISSN: 01602446     EISSN: 15334023     Source Type: Journal    
DOI: 10.1097/FJC.0b013e318256ce10     Document Type: Review

References (116)

1. Dong Y, Undyala VV, Gottlieb RA, et al. Autophagy: definition, molecular machinery, and potential role in myocardial ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther. 2010;15:220-230.
2. Prasad H, Ryan DA, Celzo MF, et al. Metabolic syndrome: definition and therapeutic implications. Postgrad Med. 2012;124:21-30.
3. Shamseddeen H, Getty JZ, Hamdallah IN, et al. Epidemiology and economic impact of obesity and type 2 diabetes. Surg Clin North Am. 2011;91:1163-1172, vii.
4. Ma D, Panda S, Lin JD. Temporal orchestration of circadian autophagy rhythm by C/EBPbeta. EMBO J. 2011;30:4642-44651.
5. Pfeifer U, Strauss P. Autophagic vacuoles in heart muscle and liver. A comparative morphometric study including circadian variations in mealfed rats. J Mol Cell Cardiol. 1981;13:37-49.
6. Pfeifer U. Inverted diurnal rhythm of cellular autophagy in liver cells of rats fed a single daily meal. Virchows Arch B Cell Pathol. 1972;10: 1-3.
7. Mizushima N, Yamamoto A, Matsui M, et al. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004; 15:1101-1111.
8. Wohlgemuth SE, Julian D, Akin DE, et al. Autophagy in the heart and liver during normal aging and calorie restriction. Rejuvenation Res. 2007;10:281-292.
9. Shinmura K, Tamaki K, Saito K, et al. Cardioprotective effects of shortterm caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase. Circulation. 2007;116:2809-2817.
10. Shinmura K, Tamaki K, Bolli R. Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxidedependent increase in nuclear Sirt1. Am J Physiol Heart Circ Physiol. 2008;295:H2348- H2355.
11. Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol. 2005;39: 285-296.
12. Liu HY, Han J, Cao SY, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284:31484-31492.
13. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007;59:418-458.
14. Gottlieb RA, Finley KD, Mentzer RM Jr. Cardioprotection requires taking out the trash. Basic Res Cardiol. 2009;104:169-180.
15. Gottlieb RA, Gustafsson AB. Mitochondrial turnover in the heart. Biochim Biophys Acta. 2011;1813:1295-1301.
16. Gottlieb RA, Mentzer RM Jr, Linton PJ. Impaired mitophagy at the heart of injury. Autophagy. 2011;7:1573-1574.
17. Gurusamy N, Lekli I, Gorbunov NV, et al. Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein. J Cell Mol Med. 2009;13:373-387.
18. Gurusamy N, Lekli I, Mukherjee S, et al. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovascular Res. 2010;86:103-112.
19. Huang C, Andres AM, Ratliff EP, et al. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS One. 2011;6:e20975.
20. Huang C, Liu W, Perry CN, et al. Autophagy and protein kinase C are required for cardioprotection by sulfaphenazole. Am J Physiol Heart Circ Physiol. 2010;298:H570-H579.
21. Huang C, Yitzhaki S, Perry CN, et al. Autophagy induced by ischemic preconditioning is essential for cardioprotection. J Cardiovasc Transl Res. 2010;3:365-373.
22. Kanamori H, Takemura G, Goto K, et al. The role of autophagy emerging in postinfarction cardiac remodelling. Cardiovascular Res. 2011;91: 330-339.
23. Sala-Mercado JA, Wider J, Undyala VV, et al. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation. 2010;122(11 suppl): S179-S184.
24. Yitzhaki S, Huang C, Liu W, et al. Autophagy is required for preconditioning by the adenosine A1 receptor-selective agonist CCPA. Basic Res Cardiol. 2009;104:157-167.
25. Zhai P, Sciarretta S, Galeotti J, et al. Differential roles of GSK-3beta during myocardial ischemia and ischemia/reperfusion. Circ Res. 2011; 109:502-511.
26. Rothermel BA, Hill JA. Autophagy in load-induced heart disease. Circ Res. 2008;103:1363-1369.
27. Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007;100:914-922.
28. Foyil SA, Ma X, Hill JA, et al. BNIP3 induced autophagy contributes to adverse ventricular remodeling. J Cardiac Failure. 2010;16(suppl):S35.
29. Khan S, Salloum F, Das A, et al. Rapamycin confers preconditioninglike protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. J Mol Cell Cardiol. 2006;41:256-264.
30. Das A, Durrant D, Salloum FN, et al. Abstract 14374: chronic treatment with rapamycin attenuates diabetes-associated adverse effects and protects against myocardial ischemia/reperfusion injury in type ii diabetic mice. Circulation. 2011;124:A14374.
31. Zhai P, Sadoshima J. Glycogen synthase kinase-3beta controls autophagy during myocardial ischemia and reperfusion. Autophagy. 2012;8: 138-139.
32. Zhu H, Tannous P, Johnstone JL, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest. 2007;117: 1782-1793.
33. Zhang D, Contu R, Latronico MV, et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest. 2010;120:2805-2816.
34. Shende P, Plaisance I, Morandi C, et al. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation. 2011;123:1073-1082.
35. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12: 21-35.
36. Sciarretta S, Zhai P, Shao D, et al. Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome. Circulation. 2012;125: 1134-1146.
37. Yan L, Sadoshima J, Vatner DE, et al. Autophagy in ischemic preconditioning and hibernating myocardium. Autophagy. 2009;5:709-712.
38. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2001;281:H1630-H1636.
39. Lee TM, Su SF, Chou TF, et al. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation. 2002;105: 334-340.
40. Bach M, Larance M, James DE, et al. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem J. 2011;40:283-291.
41. Wang Y, Gao E, Tao L, et al. AMP-activated protein kinase deficiency enhances myocardial ischemia/reperfusion injury but has minimal effect on the antioxidant/antinitrative protection of adiponectin. Circulation. 2009;119:835-844.
42. Wang J, Yang L, Rezaie AR, et al. Activated protein C protects against myocardial ischemic/reperfusion injury through AMP-activated protein kinase signaling. J Thromb Haemost. 2011;9:1308-1317.
43. Solskov L, Lofgren B, Kristiansen SB, et al. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration. Basic Clin Pharmacol Toxicol. 2008;103: 82-87.
44. Paiva MA, Goncalves LM, Providencia LA, et al. Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction. Cardiovasc Drugs Ther. 2010;24:25-32.
45. Morrison A, Yan X, Tong C, et al. Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice. Am J Physiol Heart Circ Physiol. 2011;301:H895-H902.
46. Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011;70:92-99.
47. Wang XF, Zhang JY, Li L, et al. Metformin improves cardiac function in rats via activation of AMP-activated protein kinase. Clin Exp Pharmacol Physiol. 2011;38:94-101.
48. Gundewar S, Calvert JW, Jha S, et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res. 2009;104:403-411.
49. Buss SJ, Muenz S, Riffel JH, et al. Beneficial effects of Mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J Am Coll Cardiol. 2009;54:2435-2446.
50. Nakai A, Yamaguchi O, Takeda T, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007;13:619-624.
51. Panchal SK, Brown L. Rodent models for metabolic syndrome research. J Biomed Biotechnol. 2011;2011:351982.
52. Varga O, Harangi M, Olsson IA, et al. Contribution of animal models to the understanding of the metabolic syndrome: a systematic overview. Obes Rev. 2010;11:792-807.
53. Malik SA, Marino G, Benyounes A, et al. Neuroendocrine regulation of autophagy by leptin. Cell Cycle. 2011;10:2917-2923.
54. Smith CC, Dixon RA, Wynne AM, et al. Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol. 2010;299:H1265-H1270.
55. Galvao TF, Brown BH, Hecker PA, et al. High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects. Cardiovascular Res. 2012; 93:24-32.
56. Okere IC, Chess DJ, McElfresh TA, et al. High-fat diet prevents cardiac hypertrophy and improves contractile function in the hypertensive dahl salt-sensitive rat. Clin Exp Pharmacol Physiol. 2005;32:825-831.
57. Panchal SK, Poudyal H, Iyer A, et al. High-carbohydrate, high-fat dietinduced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol. 2011;57:611-624.
58. Yang L, Li P, Fu S, et al. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010; 11:467-478.
59. French CJ, Tarikuz Zaman A, McElroy-Yaggy KL, et al. Absence of altered autophagy after myocardial ischemia in diabetic compared with nondiabetic mice. Coron Artery Dis. 2011;22:479-483.
60. Mei S, Ni HM, Manley S, et al. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J Pharmacol Exp Ther. 2011;339:487-498.
61. Zhou L, Zhang J, Fang Q, et al. Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance. Mol Pharmacol. 2009;76:596-603.
62. Kovsan J, Bluher M, Tarnovscki T, et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab. 2011;96: E268-E277.
63. Meng Q, Cai D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the I{kappa}B kinase {beta} (IKK{beta})/ NF-{kappa}B pathway. J Biol Chem. 2011;286:32324-32332.
64. Kaniuk NA, Kiraly M, Bates H, et al. Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes. 2007;56:930-939.
65. Xie Z, Lau K, Eby B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011;60:1770-1778.
66. Georgescu SP, Aronovitz MJ, Iovanna JL, et al. Decreased metalloprotease 9 induction, cardiac fibrosis and higher autophagy after pressure overload in mice lacking the transcriptional regulator p8. Am J Physiol Cell Physiol. 2011;301:C1045-C1056.
67. Deng JY, Huang JP, Lu LS, et al. Impairment of cardiac insulin signaling and myocardial contractile performance in high-cholesterol/fructose-fed rats. Am J Physiol Heart Circ Physiol. 2007;293:H978-H987.
68. Glazer HP, Osipov RM, Clements RT, et al. Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling. Cell Cycle. 2009;8:1738-1746.
69. Ko HJ, Zhang Z, Jung DY, et al. Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart. Diabetes. 2009;58:2536-2546.
70. Kelley DE, He J, Menshikova EV, et al. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51: 2944-2950.
71. Wiederkehr A, Wollheim CB. Minireview: implication of mitochondria in insulin secretion and action. Endocrinology. 2006;147:2643-2649.
72. Hojlund K, Mogensen M, Sahlin K, et al. Mitochondrial dysfunction in type 2 diabetes and obesity. Endocrinol Metab Clin North Am. 2008;37: 713-731, x.
73. Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116:434-448.
74. Abdul-Ghani MA, DeFronzo RA. Mitochondrial dysfunction, insulin resistance, and type 2 diabetes mellitus. Curr Diab Rep. 2008;8: 173-178.
75. De Pauw A, Tejerina S, Raes M, et al. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol. 2009;175:927-939.
76. Finocchietto PV, Holod S, Barreyro F, et al. Defective leptin-AMPdependent kinase pathway induces nitric oxide release and contributes to mitochondrial dysfunction and obesity in ob/ob Mice. Antioxid Redox Signal. 2011;15:2395-2406.
77. Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004; 114:1752-1761.
78. Hansel B, Giral P, Nobecourt E, et al. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab. 2004;89:4963-4971.
79. Karamouzis I, Pervanidou P, Berardelli R, et al. Enhanced oxidative stress and platelet activation combined with reduced antioxidant capacity in obese prepubertal and adolescent girls with full or partial metabolic syndrome. Horm Metab Res. 2011;43:607-613.
80. Flachs P, Ruhl R, Hensler M, et al. Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. Diabetologia. 2011; 54:2626-2638.
81. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306:457-461.
82. Iqbal J, Dai K, Seimon T, et al. IRE1beta inhibits chylomicron production by selectively degrading MTP mRNA. Cell Metab. 2008;7: 445-455.
83. Zhao H, Wang Y, Wu Y, et al. Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/ reperfusion injury and the involvement of hypoxia inducible factor- 1alpha upregulation. Acta Biochim Biophys Sin (Shanghai). 2009;41: 745-753.
84. Yi W, Sun Y, Gao E, et al. Reduced cardioprotective action of adiponectin in high-fat diet-induced type II diabetic mice and its underlying mechanisms. Antioxid Redox Signal. 2011;15:1779-1788.
85. Paulson DJ. The diabetic heart is more sensitive to ischemic injury. Cardiovascular Res. 1997;34:104-112.
86. Kersten JR, Toller WG, Gross ER, et al. Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality. Am J Physiol Heart Circ Physiol. 2000;278:H1218-H1224.
87. del Valle HF, Lascano EC, Negroni JA, et al. Absence of ischemic preconditioning protection in diabetic sheep hearts: role of sarcolemmal KATP channel dysfunction. Mol Cell Biochem. 2003;249:21-30.
88. Nieszner E, Posa I, Kocsis E, et al. Influence of diabetic state and that of different sulfonylureas on the size of myocardial infarction with and without ischemic preconditioning in rabbits. Exp Clin Endocrinol Diabetes. 2002;110:212-218.
89. Tosaki A, Pali T, Droy-Lefaix MT. Effects of Ginkgo biloba extract and preconditioning on the diabetic rat myocardium. Diabetologia. 1996;39: 1255-1262.
90. Ravingerova T, Stetka R, Volkovova K, et al. Acute diabetes modulates response to ischemia in isolated rat heart. Mol Cell Biochem. 2000;210: 143-151.
91. Sivaraman V, Hausenloy DJ, Wynne AM, et al. Preconditioning the diabetic human myocardium. J Cell Mol Med. 2010;14:1740-1746.
92. Ravingerova T, Stetka R, Pancza D, et al. Susceptibility to ischemiainduced arrhythmias and the effect of preconditioning in the diabetic rat heart. Physiol Res. 2000;49:607-616.
93. Tsang A, Hausenloy DJ, Mocanu MM, et al. Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes. 2005;54: 2360-2364.
94. Yadav HN, Singh M, Sharma PL. Modulation of the cardioprotective effect of ischemic preconditioning in hyperlipidaemic rat heart. Eur J Pharmacol. 2010;643:78-83.
95. Giricz Z, Lalu MM, Csonka C, et al. Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. J Pharmacol Exp Ther. 2006;316: 154-161.
96. Tang XL, Takano H, Xuan YT, et al. Hypercholesterolemia abrogates late preconditioning via a tetrahydrobiopterin-dependent mechanism in conscious rabbits. Circulation. 2005;112:2149-2156.
97. Kupai K, Csonka C, Fekete V, et al. Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Am J Physiol Heart Circ Physiol. 2009;297: H1729-H1735.
98. Bouhidel O, Pons S, Souktani R, et al. Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol. 2008;295:H1580-H1586.
99. Wagner C, Kloeting I, Strasser RH, et al. Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta. J Cardiovasc Pharmacol. 2008;52: 430-437.
100. Giricz Z, Gorbe A, Pipis J, et al. Hyperlipidaemia induced by a highcholesterol diet leads to the deterioration of guanosine-3',5'-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats. Br J Pharmacol. 2009;158:1495-1502.
101. Yue TL, Bao W, Gu JL, et al. Rosiglitazone treatment in Zucker diabetic Fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes. 2005;54:554-562.
102. Bhamra GS, Hausenloy DJ, Davidson SM, et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008;103:274-284.
103. Calvert JW, Gundewar S, Jha S, et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes. 2008;57:696-705.
104. Paiva MA, Rutter-Locher Z, Goncalves LM, et al. Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury. Am J Physiol Heart Circ Physiol. 2011;300:H2123-H2134.
105. Wu JM, Hsieh TC. Resveratrol: a cardioprotective substance. Ann N Y Acad Sci. 2011;1215:16-21.
106. Wu Y, Li X, Zhu JX, et al. Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson's disease. Neurosignals. 2011;19: 163-174.
107. Robich MP, Osipov RM, Chu LM, et al. Resveratrol modifies risk factors for coronary artery disease in swine with metabolic syndrome and myocardial ischemia. Eur J Pharmacol. 2011;664:45-53.
108. Ogura Y, Iemitsu M, Naito H, et al. Single bout of running exercise changes LC3-II expression in rat cardiac muscle. Biochem Biophys Res Commun. 2011;414:756-760.
109. Hippisley-Cox J, Coupland C. Effect of statins on the mortality of patients with ischaemic heart disease: population based cohort study with nested case-control analysis. Heart. 2006;92:752-758.
110. Adameova A, Harcarova A, Matejikova J, et al. Simvastatin alleviates myocardial contractile dysfunction and lethal ischemic injury in rat heart independent of cholesterol-lowering effects. Physiol Res. 2009; 58:449-454.
111. Araki M, Motojima K. Hydrophobic statins induce autophagy in cultured human rhabdomyosarcoma cells. Biochem Biophys Res Commun. 2008;367:462-467.
112. Cheng J, Ohsaki Y, Tauchi-Sato K, et al. Cholesterol depletion induces autophagy. Biochem Biophys Res Commun. 2006;351:246-252.
113. Ghavami S, Mutawe MM, Sharma P, et al. Mevalonate cascade regulation of airway mesenchymal cell autophagy and apoptosis: a dual role for p53. PLoS One. 2011;6:e16523.
114. Cohen MV, Downey JM. Adenosine: trigger and mediator of cardioprotection. Basic Res Cardiol. 2008;103:203-215.
115. McIntosh VJ, Lasley RD. Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant? J Cardiovasc Pharmacol Ther. 2012;17:21-33.
116. Gabardi S, Baroletti SA. Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy. 2010;30:1044-1056.