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Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies

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Summary

Resveratrol, a natural phytoalexin found in wine has the potential to impact a variety of human diseases. Resveratrol like other polyphenols activates many of the same intracellular pathways as those activated by caloric restriction. It can quench reactive oxidative species, ROS and induce eNOS and iNOS expression. Resveratrol also can activate SIRT1, a NAD+-dependent deacetylase, that leads an improved in mitochondrial function, and then this procedure turns to activate the transcription factor Nrf2 that coordinates expression of key antioxidant mechanisms by binding to the antioxidant response elements. Resveratrol provides cardioprotection by triggering preconditioning and inducing autophagy. It also presents chemical similarities with estrogen and was reported to activate both nuclear and extranuclear estrogen receptors. Resveratrol treatment alleviated diabetes-induced cardiovascular system disorders via different endogeneous signaling pathways including oxidative stress/antioxidant defense system, glucose/insulin metabolism, overexpression of iNOS/nitrotyrosine, and preconditioning. Resveratrol treatment significantly reduced the blood glucose level in STZ-treated type 1 diabetic animals through insulin-dependent and insulin-independent pathways. Resveratrol triggers some of the similar intracellular insulin signalling components in myocardium such as eNOS, AKT through the AMPK pathway, and plays an essential role in Glut-4 translocation and glucose uptake in STZ-induced diabetic myocardium. However, resveratrol can exhibit hormetic action expressing health benefits at lower doses whereas being detrimental at higher doses. It might also exert antidiabetic effects by activating SIRT1 directly in the brain. This review includes a summary of the role of resveratrol and diabetic cardiac function including a brief discussion on in vitro and in vivo studies as well as our original observations in diabetic rats.

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References

  • Alnaeb ME, Thompson CS, Seifalian AM, Hamilton G, Mikhailidis DP (2007) Regional differences in the expression of nitric oxide synthase and specific receptors in the vascular tissues of control and diabetic rabbits: a pilot study. In Vivo 21:1069–1074

    CAS  Google Scholar 

  • Alvarez MC, Caldiz C, Fantinelli JC, Garciarena CD, Console GM, Chiappe de Cingolani GE, Mosca SM (2008) Is cardiac hypertrophy in spontaneously hypertensive rats the cause or the consequence of oxidative stress? Hypertens Res 31:1465–1476

    Article  Google Scholar 

  • Amour J, Brzezinska AK, Jager Z, Sullivan C, Weihrauch D, Du J, Vladic N, Shi Y, Warltier DC, Pratt PF Jr, Kersten JR (2010) Hyperglycemia adversely modulates endothelial nitric oxide synthase during anesthetic preconditioning through tetrahydrobiopterin- and heat shock protein 90-mediated mechanisms. Anesthesiology 112:576–585

    Article  CAS  Google Scholar 

  • An D, Rodrigues B (2006) Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291:H1489–H1506

    Article  CAS  Google Scholar 

  • Arrick DM, Sun H, Patel KP, Mayhan WG (2011) Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats. Am J Physiol Heart Circ Physiol 301:H696–H703

    Article  CAS  Google Scholar 

  • Ayaz M, Turan B (2006) Selenium prevents diabetes-induced alterations in [Zn2+]i and metallothionein level of rat heart via restoration of cell redox cycle. Am J Physiol Heart Circ Physiol 290:H1071–H1080

    Article  CAS  Google Scholar 

  • Ayaz M, Ozdemir S, Ugur M, Vassort G, Turan B (2004) Effects of selenium on altered mechanical and electrical cardiac activities of diabetic rat. Arch Biochem Biophys 426:83–90

    Article  CAS  Google Scholar 

  • Aydemir-Koksoy A, Bilginoglu A, Sariahmetoglu M, Schulz R, Turan B (2010) Antioxidant treatment protects diabetic rats from cardiac dysfunction by preserving contractile protein targets of oxidative stress. J Nutr Biochem 21:827–833

    Article  CAS  Google Scholar 

  • Balakumar P. & Sharma NK (2011) Healing the diabetic heart: Does myocardial preconditioning work? Cell Signal

  • Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, Gu W, Accili D (2008) SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 8:333–341

    Article  CAS  Google Scholar 

  • Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3:e2264

    Article  CAS  Google Scholar 

  • Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506

    Article  CAS  Google Scholar 

  • Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342

    Article  CAS  Google Scholar 

  • Bertelli AA, Das DK (2009) Grapes, wines, resveratrol, and heart health. J Cardiovasc Pharmacol 54:468–476

    Article  CAS  Google Scholar 

  • Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16:1246–1252

    Article  CAS  Google Scholar 

  • Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, Steele AD, Crowe H, Marmor S, Luo J, Gu W, Guarente L (2007) SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6:759–767

    Article  CAS  Google Scholar 

  • Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115:3213–3223

    Article  Google Scholar 

  • Bradamante S, Barenghi L, Piccinini F, Bertelli AA, De Jonge R, Beemster P, De Jong JW (2003) Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol 465:115–123

    Article  CAS  Google Scholar 

  • Brasnyo P, Molnar GA, Mohas M, Marko L, Laczy B, Cseh J, Mikolas E, Szijarto IA, Merei A, Halmai R, Meszaros LG, Sumegi B, Wittmann I (2011) Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr 106:383–389

    Article  CAS  Google Scholar 

  • Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625

    Article  CAS  Google Scholar 

  • Buluc M, Ayaz M, Turan B, Demirel-Yilmaz E (2007) Resveratrol-induced depression of the mechanical and electrical activities of the rat heart is reversed by glyburide: evidence for possible K(ATP) channels activation. Arch Pharm Res 30:603–607

    Article  CAS  Google Scholar 

  • Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458:1056–1060

    Article  CAS  Google Scholar 

  • Cao Z, Li Y (2004) Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. Eur J Pharmacol 489:39–48

    Article  CAS  Google Scholar 

  • Centeno-Baez C, Dallaire P, Marette A (2011) Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1. Am J Physiol Endocrinol Metab 301:E922–E930

    Article  CAS  Google Scholar 

  • Ceriello A (2003) New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 26:1589–1596

    Article  CAS  Google Scholar 

  • Chan V, Fenning A, Iyer A, Hoey A, Brown L (2011) Resveratrol improves cardiovascular function in DOCA-salt hypertensive rats. Curr Pharm Biotechnol 12:429–436

    Article  CAS  Google Scholar 

  • Chen CK, Pace-Asciak CR (1996) Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta. Gen Pharmacol 27:363–366

    CAS  Google Scholar 

  • Chen WP, Su MJ, Hung LM (2007) In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant. Eur J Pharmacol 554:196–204

    Article  CAS  Google Scholar 

  • Chen YR, Yi FF, Li XY, Wang CY, Chen L, Yang XC, Su PX, Cai J (2008) Resveratrol attenuates ventricular arrhythmias and improves the long-term survival in rats with myocardial infarction. Cardiovasc Drugs Ther 22:479–485

    Article  CAS  Google Scholar 

  • Chi TC, Chen WP, Chi TL, Kuo TF, Lee SS, Cheng JT, Su MJ (2007) Phosphatidylinositol-3-kinase is involved in the antihyperglycemic effect induced by resveratrol in streptozotocin-induced diabetic rats. Life Sci 80:1713–1720

    Article  CAS  Google Scholar 

  • Cresci S, Huss JM, Beitelshees AL, Jones PG, Minton MR, Dorn GW, Kelly DP, Spertus JA, McLeod HL (2010) A PPARalpha promoter variant impairs ERR-dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes. PLoS One 5:e12584

    Article  CAS  Google Scholar 

  • Csiszar A, Labinskyy N, Pinto JT, Ballabh P, Zhang H, Losonczy G, Pearson K, de Cabo R, Pacher P, Zhang C, Ungvari Z (2009) Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol 297:H13–H20

    Article  CAS  Google Scholar 

  • Das S, Das DK (2007) Anti-inflammatory responses of resveratrol. Inflamm Allergy Drug Targets 6:168–173

    Article  CAS  Google Scholar 

  • Das M, Das DK (2010) Resveratrol and cardiovascular health. Mol Aspects Med 31:503–512

    Article  CAS  Google Scholar 

  • Das DK, Sato M, Ray PS, Maulik G, Engelman RM, Bertelli AA, Bertelli A (1999) Cardioprotection of red wine: role of polyphenolic antioxidants. Drugs Exp Clin Res 25:115–120

    CAS  Google Scholar 

  • Das S, Alagappan VK, Bagchi D, Sharma HS, Maulik N, Das DK (2005a) Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrol preconditioning of the heart. Vascul Pharmacol 42:281–289

    Article  CAS  Google Scholar 

  • Das S, Cordis GA, Maulik N, Das DK (2005b) Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol 288:H328–H335

    Article  CAS  Google Scholar 

  • Das S, Tosaki A, Bagchi D, Maulik N, Das DK (2006) Potentiation of a survival signal in the ischemic heart by resveratrol through p38 mitogen-activated protein kinase/mitogen- and stress-activated protein kinase 1/cAMP response element-binding protein signaling. J Pharmacol Exp Ther 317:980–988

    Article  CAS  Google Scholar 

  • Dolinsky VW, Dyck JR (2006) Role of AMP-activated protein kinase in healthy and diseased hearts. Am J Physiol Heart Circ Physiol 291:H2557–H2569

    Article  CAS  Google Scholar 

  • Dolinsky VW, Dyck JR (2011) Calorie restriction and resveratrol in cardiovascular health and disease. Biochim Biophys Acta 1812:1477–1489

    CAS  Google Scholar 

  • Dolinsky VW, Chan AY, Robillard Frayne I, Light PE, Des Rosiers C, Dyck JR (2009) Resveratrol prevents the prohypertrophic effects of oxidative stress on LKB1. Circulation 119:1643–1652

    Article  CAS  Google Scholar 

  • Dudley J, Das S, Mukherjee S, Das DK (2009) Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J Nutr Biochem 20:443–452

    Article  CAS  Google Scholar 

  • Duncan JG, Fong JL, Medeiros DM, Finck BN, Kelly DP (2007) Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation 115:909–917

    Article  CAS  Google Scholar 

  • El-Mowafy AM, White RE (1999) Resveratrol inhibits MAPK activity and nuclear translocation in coronary artery smooth muscle: reversal of endothelin-1 stimulatory effects. FEBS Lett 451:63–67

    Article  CAS  Google Scholar 

  • Ersoz G, Yakaryilmaz A, Turan B (2003) Effect of sodium selenite treatment on platelet aggregation of streptozotocin-induced diabetic rats. Thromb Res 111:363–367

    Article  CAS  Google Scholar 

  • Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J (2008) Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 8:347–358

    Article  CAS  Google Scholar 

  • Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130

    CAS  Google Scholar 

  • Forstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5:338–349

    Article  CAS  Google Scholar 

  • Fremont L, Belguendouz L, Delpal S (1999) Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. Life Sci 64:2511–2521

    Article  CAS  Google Scholar 

  • Frojdo S, Cozzone D, Vidal H, Pirola L (2007) Resveratrol is a class IA phosphoinositide 3-kinase inhibitor. Biochem J 406:511–518

    Article  CAS  Google Scholar 

  • Gadacha W, Ben-Attia M, Bonnefont-Rousselot D, Aouani E, Ghanem-Boughanmi N, Touitou Y (2009) Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night. Redox Rep 14:154–158

    Article  CAS  Google Scholar 

  • Gehm BD, McAndrews JM, Chien PY, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci U S A 94:14138–14143

    Article  CAS  Google Scholar 

  • Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 26:1913–1923

    Article  CAS  Google Scholar 

  • Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, Chaudhuri A, Dandona P (2011) A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab 96:1409–1414

    Article  CAS  Google Scholar 

  • Goh SS, Woodman OL, Pepe S, Cao AH, Qin C, Ritchie RH (2007) The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms. Antioxid Redox Signal 9:101–113

    Article  CAS  Google Scholar 

  • Gorbunov N, Petrovski G, Gurusamy N, Ray D, Kim DH. & Das DK (2011) Regeneration of Infarcted Myocardium with Resveratrol-Modified Cardiac Stem Cells. J Cell Mol Med

  • Gresele P, Cerletti C, Guglielmini G, Pignatelli P, de Gaetano G, Violi F (2011) Effects of resveratrol and other wine polyphenols on vascular function: an update. J Nutr Biochem 22:201–211

    Article  CAS  Google Scholar 

  • Gurusamy N, Ray D, Lekli I, Das DK (2010) Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. J Cell Mol Med 14:2235–2239

    Article  Google Scholar 

  • Halliwell B (2007) Dietary polyphenols: good, bad, or indifferent for your health? Cardiovasc Res 73:341–347

    Article  CAS  Google Scholar 

  • Hattori R, Otani H, Maulik N, Das DK (2002) Pharmacological preconditioning with resveratrol: role of nitric oxide. Am J Physiol Heart Circ Physiol 282:H1988–H1995

    CAS  Google Scholar 

  • He X, Chen MG, Lin GX, Ma Q (2006) Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 x Keap1 x Cul3 complex and recruiting Nrf2 x Maf to the antioxidant response element enhancer. J Biol Chem 281:23620–23631

    Article  CAS  Google Scholar 

  • He X, Kan H, Cai L, Ma Q (2009) Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol 46:47–58

    Article  CAS  Google Scholar 

  • Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196

    Article  CAS  Google Scholar 

  • Hsieh TC, Juan G, Darzynkiewicz Z, Wu JM (1999) Resveratrol increases nitric oxide synthase, induces accumulation of p53 and p21(WAF1/CIP1), and suppresses cultured bovine pulmonary artery endothelial cell proliferation by perturbing progression through S and G2. Cancer Res 59:2596–2601

    CAS  Google Scholar 

  • Huang JP, Huang SS, Deng JY, Chang CC, Day YJ, Hung LM (2010) Insulin and resveratrol act synergistically, preventing cardiac dysfunction in diabetes, but the advantage of resveratrol in diabetics with acute heart attack is antagonized by insulin. Free Radic Biol Med 49:1710–1721

    Article  CAS  Google Scholar 

  • Hung LM, Chen JK, Huang SS, Lee RS, Su MJ (2000) Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 47:549–555

    Article  CAS  Google Scholar 

  • Hung LM, Su MJ, Chen JK (2004) Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms. Free Radic Biol Med 36:774–781

    Article  CAS  Google Scholar 

  • Hwang JT, Kwon DY, Park OJ, Kim MS (2008) Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr 2:323–326

    Article  CAS  Google Scholar 

  • Imamura G, Bertelli AA, Bertelli A, Otani H, Maulik N, Das DK (2002) Pharmacological preconditioning with resveratrol: an insight with iNOS knockout mice. Am J Physiol Heart Circ Physiol 282:H1996–H2003

    CAS  Google Scholar 

  • Jennings RB, Murry CE, Reimer KA (1991) Preconditioning myocardium with ischemia. Cardiovasc Drugs Ther 5:933–938

    Article  CAS  Google Scholar 

  • Jing YH, Chen KH, Yang SH, Kuo PC, Chen JK (2010) Resveratrol ameliorates vasculopathy in STZ-induced diabetic rats: role of AGE-RAGE signalling. Diabetes Metab Res Rev 26:212–222

    Article  CAS  Google Scholar 

  • Juric D, Wojciechowski P, Das DK, Netticadan T (2007) Prevention of concentric hypertrophy and diastolic impairment in aortic-banded rats treated with resveratrol. Am J Physiol Heart Circ Physiol 292:H2138–H2143

    Article  CAS  Google Scholar 

  • Kao CL, Chen LK, Chang YL, Yung MC, Hsu CC, Chen YC, Lo WL, Chen SJ, Ku HH, Hwang SJ (2010) Resveratrol protects human endothelium from H(2)O(2)-induced oxidative stress and senescence via SirT1 activation. J Atheroscler Thromb 17:970–979

    Article  CAS  Google Scholar 

  • Kar P, Laight D, Rooprai HK, Shaw KM, Cummings M (2009) Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med 26:526–531

    Article  CAS  Google Scholar 

  • Kennedy DO, Wightman EL, Reay JL, Lietz G, Okello EJ, Wilde A, Haskell CF (2010) Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am J Clin Nutr 91:1590–1597

    Article  CAS  Google Scholar 

  • Khan NQ, Lees DM, Douthwaite JA, Carrier MJ, Corder R (2002) Comparison of red wine extract and polyphenol constituents on endothelin-1 synthesis by cultured endothelial cells. Clin Sci Lond 103(48):72S–75S

    CAS  Google Scholar 

  • Kiziltepe U, Turan NN, Han U, Ulus AT, Akar F (2004) Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J Vasc Surg 40:138–145

    Article  Google Scholar 

  • Klinge CM, Blankenship KA, Risinger KE, Bhatnagar S, Noisin EL, Sumanasekera WK, Zhao L, Brey DM, Keynton RS (2005) Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 280:7460–7468

    Article  CAS  Google Scholar 

  • Klinge CM, Wickramasinghe NS, Ivanova MM, Dougherty SM (2008) Resveratrol stimulates nitric oxide production by increasing estrogen receptor alpha-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J 22:2185–2197

    Article  CAS  Google Scholar 

  • Knight CM, Gutierrez-Juarez R, Lam TK, Arrieta-Cruz I, Huang L, Schwartz G, Barzilai N. & Rossetti L (2011) Mediobasal hypothalamic Sirtuin 1 is essential for resveratrol’s effects on insulin action in rats. Diabetes

  • Kovacic P, Somanathan R (2010) Multifaceted approach to resveratrol bioactivity: Focus on antioxidant action, cell signaling and safety. Oxid Med Cell Longev 3:86–100

    Article  Google Scholar 

  • Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122

    Article  CAS  Google Scholar 

  • Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (2011) Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection. J Pineal Res 50:374–380

    Article  CAS  Google Scholar 

  • Leikert JF, Rathel TR, Wohlfart P, Cheynier V, Vollmar AM, Dirsch VM (2002) Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation 106:1614–1617

    Article  CAS  Google Scholar 

  • Lekakis J, Rallidis LS, Andreadou I, Vamvakou G, Kazantzoglou G, Magiatis P, Skaltsounis AL, Kremastinos DT (2005) Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil 12:596–600

    Article  Google Scholar 

  • Lekli I, Szabo G, Juhasz B, Das S, Das M, Varga E, Szendrei L, Gesztelyi R, Varadi J, Bak I, Das DK, Tosaki A (2008) Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol 294:H859–H866

    Article  CAS  Google Scholar 

  • Lekli I, Ray D, Mukherjee S, Gurusamy N, Ahsan MK, Juhasz B, Bak I, Tosaki A, Gherghiceanu M, Popescu LM, & Das DK. Co-ordinated autophagy with resveratrol and gamma-tocotrienol confers synergetic cardioprotection, J Cell Mol Med. 14: 2506–18.

  • Li Y, Cao Z, Zhu H (2006) Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacol Res 53:6–15

    Article  CAS  Google Scholar 

  • Li Q, Li J, Ren J (2009) UCF-101 mitigates streptozotocin-induced cardiomyocyte dysfunction: role of AMPK. Am J Physiol Endocrinol Metab 297:E965–E973

    Article  CAS  Google Scholar 

  • Liew R, Stagg MA, MacLeod KT, Collins P (2005) The red wine polyphenol, resveratrol, exerts acute direct actions on guinea-pig ventricular myocytes. Eur J Pharmacol 519:1–8

    Article  CAS  Google Scholar 

  • Liu Y, Sato T, O’Rourke B, Marban E (1998) Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation 97:2463–2469

    CAS  Google Scholar 

  • Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280:37377–37382

    Article  CAS  Google Scholar 

  • Markus MA, Morris BJ (2008) Resveratrol in prevention and treatment of common clinical conditions of aging. Clin Interv Aging 3:331–339

    CAS  Google Scholar 

  • Marques FZ, Markus MA, Morris BJ (2009) Resveratrol: cellular actions of a potent natural chemical that confers a diversity of health benefits. Int J Biochem Cell Biol 41:2125–2128

    Article  CAS  Google Scholar 

  • Matkovics B, Kotorman M, Varga IS, Hai DQ, Varga C (1997) Oxidative stress in experimental diabetes induced by streptozotocin. Acta Physiol Hung 85:29–38

    CAS  Google Scholar 

  • Michael LF, Wu Z, Cheatham RB, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci U S A 98:3820–3825

    Article  CAS  Google Scholar 

  • Min Z, Kang L, Lin L, Jinghua F, Junna S, Baolin L (2010) Resveratrol restores lysophosphatidylcholine-induced loss of endothelium-dependent relaxation in rat aorta tissue coinciding with inhibition of extracellular-signal-regulated protein kinase activation. Phytother Res 24:1762–1768

    Article  CAS  Google Scholar 

  • Mizutani K, Ikeda K, Kawai Y, Yamori Y (2001) Protective effect of resveratrol on oxidative damage in male and female stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 28:55–59

    Article  CAS  Google Scholar 

  • Mukherjee S, Ray D, Lekli I, Bak I, Tosaki A, Das DK (2010) Effects of Longevinex (modified resveratrol) on cardioprotection and its mechanisms of action. Can J Physiol Pharmacol 88:1017–1025

    Article  CAS  Google Scholar 

  • Mukhopadhyay P, Mukherjee S, Ahsan K, Bagchi A, Pacher P, Das DK (2010) Restoration of altered microRNA expression in the ischemic heart with resveratrol. PLoS One 5:e15705

    Article  CAS  Google Scholar 

  • Murphy E (2011) Estrogen signaling and cardiovascular disease. Circ Res 109:687–696

    Article  CAS  Google Scholar 

  • Naderali EK, Doyle PJ, Williams G (2000) Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs. Clin Sci (Lond) 98:537–543

    Article  CAS  Google Scholar 

  • Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, Holcombe RF (2009) Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res 1:25–37

    CAS  Google Scholar 

  • Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285:8340–8351

    Article  CAS  Google Scholar 

  • Palsamy P, Subramanian S (2011) Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta 1812:719–731

    CAS  Google Scholar 

  • Parratt JR, Kane KA (1994) KATP channels in ischaemic preconditioning. Cardiovasc Res 28:783–787

    Article  CAS  Google Scholar 

  • Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K (2011) Clinical trials of resveratrol. Ann N Y Acad Sci 1215:161–169

    Article  CAS  Google Scholar 

  • Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157–168

    Article  CAS  Google Scholar 

  • Penumathsa SV, Thirunavukkarasu M, Zhan L, Maulik G, Menon VP, Bagchi D, Maulik N (2008) Resveratrol enhances GLUT-4 translocation to the caveolar lipid raft fractions through AMPK/Akt/eNOS signalling pathway in diabetic myocardium. J Cell Mol Med 12:2350–2361

    Article  CAS  Google Scholar 

  • Pervaiz S, Holme AL (2009) Resveratrol: its biologic targets and functional activity. Antioxid Redox Signal 11:2851–2897

    Article  CAS  Google Scholar 

  • Petrovski G, Gurusamy N, Das DK (2011) Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci 1215:22–33

    Article  CAS  Google Scholar 

  • Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH (2008) Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 105:9793–9798

    Article  CAS  Google Scholar 

  • Pirola L, Frojdo S (2008) Resveratrol: one molecule, many targets. IUBMB Life 60:323–332

    Article  CAS  Google Scholar 

  • Rahangdale S, Yeh SY, Malhotra A, Veves A (2009) Therapeutic interventions and oxidative stress in diabetes. Front Biosci 14:192–209

    Article  CAS  Google Scholar 

  • Ramadori G, Gautron L, Fujikawa T, Vianna CR, Elmquist JK, Coppari R (2009) Central administration of resveratrol improves diet-induced diabetes. Endocrinology 150:5326–5333

    Article  CAS  Google Scholar 

  • Ranhotra HS (2010) The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions. J Recept Signal Transduct Res 30:193–205

    Article  CAS  Google Scholar 

  • Ray PS, Maulik G, Cordis GA, Bertelli AA, Bertelli A, Das DK (1999) The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 27:160–169

    Article  CAS  Google Scholar 

  • Renaud S, de Lorgeril M (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339:1523–1526

    Article  CAS  Google Scholar 

  • Robich MP, Osipov RM, Nezafat R, Feng J, Clements RT, Bianchi C, Boodhwani M, Coady MA, Laham RJ, Sellke FW (2010) Resveratrol improves myocardial perfusion in a swine model of hypercholesterolemia and chronic myocardial ischemia. Circulation 122:S142–S149

    Article  CAS  Google Scholar 

  • Roghani M, Baluchnejadmojarad T (2010) Mechanisms underlying vascular effect of chronic resveratrol in streptozotocin-diabetic rats. Phytother Res 24(Suppl 2):S148–S154

    Article  Google Scholar 

  • Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD (2006) Chronic activation of PPARalpha is detrimental to cardiac recovery after ischemia. Am J Physiol Heart Circ Physiol 290:H87–H95

    Article  CAS  Google Scholar 

  • Schilling J, Kelly DP (2011) The PGC-1 cascade as a therapeutic target for heart failure. J Mol Cell Cardiol 51:578–583

    Article  CAS  Google Scholar 

  • Sebai H, Ben-Attia M, Sani M, Aouani E, Ghanem-Boughanmi N (2008) Protective effect of resveratrol on acute endotoxemia-induced nephrotoxicity in rat through nitric oxide independent mechanism. Free Radic Res 42:913–920

    Article  CAS  Google Scholar 

  • Shakibaei M, Harikumar KB, Aggarwal BB (2009) Resveratrol addiction: to die or not to die. Mol Nutr Food Res 53:115–128

    Article  CAS  Google Scholar 

  • Siemann E, Creasy L (1992) Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic 43:49–52

    CAS  Google Scholar 

  • Smoliga JM, Vang O. & Baur JA (2011) Challenges of translating basic research into therapeutics: Resveratrol as an example. J Gerontol A Biol Sci Med Sci

  • Smoliga JM, Baur JA, Hausenblas HA (2011b) Resveratrol and health–a comprehensive review of human clinical trials. Mol Nutr Food Res 55:1129–1141

    Article  CAS  Google Scholar 

  • Soylemez S, Sepici A, Akar F (2009) Resveratrol supplementation gender independently improves endothelial reactivity and suppresses superoxide production in healthy rats. Cardiovasc Drugs Ther 23:449–458

    Article  CAS  Google Scholar 

  • Spanier G, Xu H, Xia N, Tobias S, Deng S, Wojnowski L, Forstermann U, Li H (2009) Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4). J Physiol Pharmacol 60(Suppl 4):111–116

    Google Scholar 

  • Su HC, Hung LM, Chen JK (2006) Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 290:E1339–E1346

    Article  CAS  Google Scholar 

  • Sulaiman M, Matta MJ, Sunderesan NR, Gupta MP, Periasamy M, Gupta M (2010) Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 298:H833–H843

    Article  CAS  Google Scholar 

  • Tan Y, Ichikawa T, Li J, Si Q, Yang H, Chen X, Goldblatt CS, Meyer CJ, Li X, Cai L, Cui T (2011) Diabetic downregulation of Nrf2 activity via ERK contributes to oxidative stress-induced insulin resistance in cardiac cells in vitro and in vivo. Diabetes 60:625–633

    Article  CAS  Google Scholar 

  • Tanno M, Tsuchida A, Nozawa Y, Matsumoto T, Hasegawa T, Miura T, Shimamoto K (2000) Roles of tyrosine kinase and protein kinase C in infarct size limitation by repetitive ischemic preconditioning in the rat. J Cardiovasc Pharmacol 35:345–352

    Article  CAS  Google Scholar 

  • Thandapilly SJ, Wojciechowski P, Behbahani J, Louis XL, Yu L, Juric D, Kopilas MA, Anderson HD, Netticadan T (2010) Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure. Am J Hypertens 23:192–196

    Article  CAS  Google Scholar 

  • Thirunavukkarasu M, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, Bagchi D, Das DK, Maulik N (2007) Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. Free Radic Biol Med 43:720–729

    Article  CAS  Google Scholar 

  • Toklu HZ, Sehirli O, Ersahin M, Suleymanoglu S, Yiginer O, Emekli-Alturfan E, Yarat A, Yegen BC, Sener G (2010) Resveratrol improves cardiovascular function and reduces oxidative organ damage in the renal, cardiovascular and cerebral tissues of two-kidney, one-clip hypertensive rats. J Pharm Pharmacol 62:1784–1793

    Article  CAS  Google Scholar 

  • Torres MD, Canal JR, Perez C (1999) Oxidative stress in normal and diabetic rats. Physiol Res 48:203–208

    CAS  Google Scholar 

  • Tsuchida A, Miura T, Tanno M, Sakamoto J, Miki T, Kuno A, Matsumoto T, Ohnuma Y, Ichikawa Y, Shimamoto K (2002) Infarct size limitation by nicorandil: roles of mitochondrial K(ATP) channels, sarcolemmal K(ATP) channels, and protein kinase C. J Am Coll Cardiol 40:1523–1530

    Article  CAS  Google Scholar 

  • Turan B, Hotomaroglu O, Kilic M, Demirel-Yilmaz E (1999) Cardiac dysfunction induced by low and high diet antioxidant levels comparing selenium and vitamin E in rats. Regul Toxicol Pharmacol 29:142–150

    Article  CAS  Google Scholar 

  • Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH (2010) AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 59:554–563

    Article  CAS  Google Scholar 

  • Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z, Olson S, Podlutsky A, Csiszar A (2007) Resveratrol increases vascular oxidative stress resistance. Am J Physiol Heart Circ Physiol 292:H2417–H2424

    Article  CAS  Google Scholar 

  • Ungvari Z, Labinskyy N, Mukhopadhyay P, Pinto JT, Bagi Z, Ballabh P, Zhang C, Pacher P, Csiszar A (2009) Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol 297:H1876–H1881

    Article  CAS  Google Scholar 

  • Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, de Cabo R, Csiszar A (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299:H18–H24

    Article  CAS  Google Scholar 

  • Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:296–300

    Article  CAS  Google Scholar 

  • Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, Das DK, Delmas D, Gottfried C, Lin HY, Ma QY, Mukhopadhyay P, Nalini N, Pezzuto JM, Richard T, Shukla Y, Surh YJ, Szekeres T, Szkudelski T, Walle T, Wu JM (2011) What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One 6:e19881

    Article  CAS  Google Scholar 

  • Wallenborg K, Vlachos P, Eriksson S, Huijbregts L, Arner ES, Joseph B, Hermanson O (2009) Red wine triggers cell death and thioredoxin reductase inhibition: effects beyond resveratrol and SIRT1. Exp Cell Res 315:1360–1371

    Article  CAS  Google Scholar 

  • Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, Forstermann U (2002) Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 106:1652–1658

    Article  CAS  Google Scholar 

  • Wang MY, Unger RH (2005) Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone. Am J Physiol Endocrinol Metab 288:E216–E221

    Article  CAS  Google Scholar 

  • Wang H, Yang YJ, Qian HY, Zhang Q, Xu H. & Li JJ (2011) Resveratrol in cardiovascular disease: what is known from current research?, Heart Fail Rev

  • Wong RH, Howe PR, Buckley JD, Coates AM, Kunz I, Berry NM (2011) Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis 21:851–856

    Article  CAS  Google Scholar 

  • Wu JM, Hsieh TC (2011) Resveratrol: a cardioprotective substance. Ann N Y Acad Sci 1215:16–21

    Article  CAS  Google Scholar 

  • Wu Y, Song P, Xu J, Zhang M, Zou MH (2007) Activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem 282:9777–9788

    Article  CAS  Google Scholar 

  • Xia N, Daiber A, Habermeier A, Closs EI, Thum T, Spanier G, Lu Q, Oelze M, Torzewski M, Lackner KJ, Munzel T, Forstermann U, Li H (2010) Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther 335:149–154

    Article  CAS  Google Scholar 

  • Xu Z, Patel KP, Lou MF, Rozanski GJ (2002) Up-regulation of K(+) channels in diabetic rat ventricular myocytes by insulin and glutathione. Cardiovasc Res 53:80–88

    Article  CAS  Google Scholar 

  • Yoshida H, Bao L, Kefaloyianni E, Taskin E, Okorie U, Hong M, Dhar-Chowdhury P, Kaneko M. & Coetzee WA (2011) AMP-activated protein kinase connects cellular energy metabolism to K(ATP) channel function. J Mol Cell Cardiol

  • Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA (2006) Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 55:2180–2191

    Article  CAS  Google Scholar 

  • Zeydanli EN, Kandilci HB, Turan B (2011) Doxycycline ameliorates vascular endothelial and contractile dysfunction in the thoracic aorta of diabetic rats. Cardiovasc Toxicol 11:134–147

    Article  CAS  Google Scholar 

  • Zhang Y, Liu Y, Wang T, Li B, Li H, Wang Z, Yang B (2006) Resveratrol, a natural ingredient of grape skin: antiarrhythmic efficacy and ionic mechanisms. Biochem Biophys Res Commun 340:1192–1199

    Article  CAS  Google Scholar 

  • Zhang H, Morgan B, Potter BJ, Ma L, Dellsperger KC, Ungvari Z, Zhang C (2010) Resveratrol improves left ventricular diastolic relaxation in type 2 diabetes by inhibiting oxidative/nitrative stress: in vivo demonstration with magnetic resonance imaging. Am J Physiol Heart Circ Physiol 299:H985–H994

    Article  CAS  Google Scholar 

  • Zhang C, Feng Y, Qu S, Wei X, Zhu H, Luo Q, Liu M, Chen G, Xiao X (2011) Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc Res 90:538–545

    Article  CAS  Google Scholar 

  • Zhao J, Ma HJ, Dong JH, Zhang LP, Liu HL, Wang QS (2004) Electrophysiological effects of resveratrol on guinea pig papillary muscles. Acta Physiol Sin 56:708–712

    Google Scholar 

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  1. Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey

    Belma Turan & Erkan Tuncay

  2. INSERM U-1046, Université Montpellier 1 et Université Montpellier 2, Montpellier, France

    Guy Vassort

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  1. Belma Turan
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Correspondence to Belma Turan.

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Turan, B., Tuncay, E. & Vassort, G. Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies. J Bioenerg Biomembr 44, 281–296 (2012). https://doi.org/10.1007/s10863-012-9429-0

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