Advertisement
Heart, Lung and Circulation

Evidence for a Causal Role of Oxidative Stress in the Myocardial Complications of Insulin Resistance

      Insulin resistance is a characteristic feature of type 2 diabetes and congestive heart failure. Evidence is now emerging regarding the potential for oxidative stress to play a causal role in the development of the myocardial complications of insulin resistance (analagous to its well-established in the vascular complications of diabetes). This review will specifically address whether, and by what potential mechanisms, targeting this oxidative stress might offer beneficial actions on myocardial function in the insulin-resistant heart. Antioxidant approaches, both disappointing and promising, are considered.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Heart, Lung and Circulation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • King H.
        • Aubert R.E.
        • Herman W.H.
        Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections.
        Diabetes Care. 1998; 21: 1414-1431
        • Wild S.
        • Roglic G.
        • Green A.
        • Sicree R.
        • King H.
        Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
        Diabetes Care. 2004; 27: 1047-1053
        • Jandeleit-Dahm K.A.M.
        • Tikellis C.
        • Reid C.M.
        • Johnston C.I.
        • Cooper M.E.
        Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes.
        J Hypertens. 2005; 23: 463-473
        • Devereux R.B.
        • Roman M.J.
        • Paranicas M.
        • O’Grady M.J.
        • Lee E.T.
        • Welty T.K.
        • Fabsitz R.R.
        • Robbins D.
        • Rhoades E.R.
        • Howard B.V.
        Impact of diabetes on cardiac structure and function: the strong heart study.
        Circulation. 2000; 101: 2271-2276
        • Boudina S.
        • Abel E.D.
        Diabetic cardiomyopathy revisited.
        Circulation. 2007; 115: 3213-3223
        • Rubler S.
        • Dlugash J.
        • Yuceoglu Y.Z.
        • Kumral T.
        • Branwood A.W.
        • Grishman A.
        New type of cardiomyopathy associated with diabetic glomerulosclerosis.
        Am J Cardiol. 1972; 30: 595-602
        • Ostenson C.G.
        The pathophysiology of type 2 diabetes mellitus: an overview.
        Acta Physiol Scand. 2001; 171: 241-247
        • Witteles R.M.
        • Fowler M.B.
        Insulin-resistant cardiomyopathy clinical evidence, mechanisms, and treatment options.
        J Am Coll Cardiol. 2008; 51: 93-102
        • Novoa F.J.
        • Boronat M.
        • Saavedra P.
        • Diaz-Cremades J.M.
        • Varillas V.F.
        • La Roche F.
        • Alberiche M.P.
        • Carrillo A.
        Differences in cardiovascular risk factors, insulin resistance, and insulin secretion in individuals with normal glucose tolerance and in subjects with impaired glucose regulation: the Telde Study.
        Diabetes Care. 2005; 28: 2388-2393
        • Sorescu D.
        • Griendling K.K.
        Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure.
        Congest Heart Fail. 2002; 8: 132-140
        • Beckman J.S.
        • Koppenol W.H.
        Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.
        Am J Physiol. 1996; 271: C1424-C1437
        • Cai L.
        Suppression of nitrative damage by metallothionein in diabetic heart contributes to the prevention of cardiomyopathy.
        Free Radic Biol Med. 2006; 41: 851-861
        • Mitchell J.B.
        • Samuni A.
        • Krishna M.C.
        • DeGraff W.G.
        • Ahn M.S.
        • Samuni U.
        • Russo A.
        Biologically active metal-independent superoxide dismutase mimics.
        Biochemistry. 1990; 29: 2802-2807
        • Selemidis S.
        • Sobey C.G.
        • Schmidt H.H.H.W.
        • Wingler K.
        • Drummond G.R.
        NADPH oxidases in the vasculature: molecular features, roles in disease and pharmacological inhibition.
        Pharmacol Ther. 2008; 120: 254-291
        • Brownlee M.
        Biochemistry and molecular cell biology of diabetic complications.
        Nature. 2001; 414: 813-820
        • Sawyer D.B.
        • Siwik D.A.
        • Xiao L.
        • Pimentel D.R.
        • Singh K.
        • Colucci W.S.
        Role of oxidative stress in myocardial hypertrophy and failure.
        J Mol Cell Cardiol. 2002; 34: 379-388
        • Cave A.
        • Grieve D.
        • Johar S.
        • Zhang M.
        • Shah A.M.
        NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology.
        Philos Trans R Soc Lond B Biol Sci. 2005; 360: 2327-2334
        • Ritchie R.H.
        • Delbridge L.M.D.
        Cardiac hypertrophy, substrate utilization and metabolic remodelling: cause or effect?.
        Clin Exp Pharmacol Physiol. 2006; 33: 171-178
        • Laskowski A.
        • Woodman O.L.
        • Cao A.H.
        • Drummond G.R.
        • Marshall T.
        • Kaye D.M.
        • Ritchie R.H.
        Antioxidant actions contribute to the antihypertrophic effects of atrial natriuretic peptide in neonatal rat cardiomyocytes.
        Cardiovasc Res. 2006; 72: 112-123
        • Cooper S.A.
        • Whaley-Connell A.
        • Habibi J.
        • Wei Y.
        • Lastra G.
        • Manrique C.
        • Stas S.
        • Sowers J.R.
        Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance.
        Am J Physiol Heart Circ Physiol. 2007; 293: H2009-H2023
        • Dhalla A.K.
        • Hill M.F.
        • Singal P.K.
        Role of oxidative stress in transition of hypertrophy to heart failure.
        J Am Coll Cardiol. 1996; 28: 506-514
        • Fang Z.Y.
        • Prins J.B.
        • Marwick T.H.
        Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications.
        Endocr Rev. 2004; 25: 543-567
        • Saraiva R.M.
        • Duarte D.M.
        • Duarte M.P.C.
        • Martins A.F.
        • Poltronieri A.V.G.
        • Ferreira M.E.
        • Silva M.C.
        • Hohleuwerger R.
        • Ellis A.
        • Rachid M.B.
        • Monteiro C.F.C.
        • Kaiser S.E.
        Tissue Doppler imaging identifies asymptomatic normotensive diabetics with diastolic dysfunction and reduced exercise tolerance.
        Echocardiography. 2005; 22: 561-570
        • Galderisi M.
        Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography.
        J Am Coll Cardiol. 2006; 48: 548-555
        • Fang Z.Y.
        • Najos-Valencia O.
        • Leano R.
        • Marwick T.H.
        Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine.
        J Am Coll Cardiol. 2003; 42: 611-617
        • van der Meer R.W.
        • Diamant M.
        • Westenberg J.J.M.
        • Doornbos J.
        • Bax J.J.
        • de Roos A.
        • Lamb H.J.
        Magnetic resonance assessment of aortic pulse wave velocity, aortic distensibility, and cardiac function in uncomplicated type 2 diabetes mellitus.
        J Cardiovasc Magn Reson. 2007; 9: 645-651
        • Poirier P.
        • Bogaty P.
        • Garneau C.
        • Marois L.
        • Dumesnil J.G.
        Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy.
        Diabetes Care. 2001; 24: 5-10
        • Zabalgoitia M.
        • Ismaeil M.F.
        • Anderson L.
        • Maklady F.A.
        Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus.
        Am J Cardiol. 2001; 87: 320-323
        • Di Bello V.
        • Santini F.
        • Di Cori A.
        • Pucci A.
        • Palagi C.
        • Delle Donne M.G.
        • Giannetti M.
        • Talini E.
        • Nardi C.
        • Pedrizzetti G.
        • Fierabracci P.
        • Vitti P.
        • Pinchera A.
        • Balbarini A.
        Relationship between preclinical abnormalities of global and regional left ventricular function and insulin resistance in severe obesity: a color Doppler imaging study.
        Int J Obes (Lond). 2006; 30: 948-956
        • Fischer M.
        • Baessler A.
        • Hense H.W.
        • Hengstenberg C.
        • Muscholl M.
        • Holmer S.
        • Doring A.
        • Broeckel U.
        • Riegger G.
        • Schunkert H.
        Prevalence of left ventricular diastolic dysfunction in the community—results from a Doppler echocardiographic-based survey of a population sample.
        Eur Heart J. 2003; 24: 320-328
        • Watanabe K.
        • Sekiya M.
        • Tsuruoka T.
        • Funada J.
        • Kameoka H.
        Effect of insulin resistance on left ventricular hypertrophy and dysfunction in essential hypertension.
        J Hypertens. 1999; 17: 1153-1160
        • Zizek B.
        • Poredos P.
        • Trojar A.
        • Zeljko T.
        Diastolic dysfunction is associated with insulin resistance, but not with aldosterone level in normotensive offspring of hypertensive families.
        Cardiology. 2008; 111: 8-15
        • Stewart K.J.
        • Ouyang P.
        • Bacher A.C.
        • Lima S.
        • Shapiro E.P.
        Exercise effects on cardiac size and left ventricular diastolic function: relationships to changes in fitness, fatness, blood pressure and insulin resistance.
        Heart. 2006; 92: 893-898
        • Hsu K.L.
        • Tsai C.H.
        • Chiang F.T.
        • Lo H.M.
        • Tseng C.D.
        • Wang S.M.
        • Chen C.F.
        • Tseng Y.Z.
        Myocardial mechanics and titin in experimental insulin-resistant rats.
        Jpn Heart J. 1997; 38: 717-728
        • Huggins C.E.
        • Domenighetti A.A.
        • Ritchie M.E.
        • Khalil N.
        • Favaloro J.M.
        • Proietto J.
        • Smyth G.K.
        • Pepe S.
        • Delbridge L.M.D.
        Functional and metabolic remodelling in GLUT4-deficient hearts confers hyper-responsiveness to substrate intervention.
        J Mol Cell Cardiol. 2008; 44: 270-280
        • Severson D.L.
        Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes.
        Can J Physiol Pharmacol. 2004; 82: 813-823
        • Davidoff A.J.
        • Mason M.M.
        • Davidson M.B.
        • Carmody M.W.
        • Hintz K.K.
        • Wold L.E.
        • Podolin D.A.
        • Ren J.
        Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments.
        Am J Physiol Endocrinol Metab. 2004; 286: E718-E724
        • Dutta K.
        • Podolin D.A.
        • Davidson M.B.
        • Davidoff A.J.
        Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance.
        Diabetes. 2001; 50: 1186-1192
        • Donthi R.V.
        • Ye G.
        • Wu C.
        • McClain D.A.
        • Lange A.J.
        • Epstein P.N.
        Cardiac expression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity.
        J Biol Chem. 2004; 279: 48085-48090
        • Whaley-Connell A.
        • Habibi J.
        • Cooper S.A.
        • Demarco V.G.
        • Hayden M.R.
        • Stump C.S.
        • Link D.
        • Ferrario C.M.
        • Sowers J.R.
        Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat.
        Am J Physiol Endocrinol Metab. 2008; 295: E103-E109
        • Whaley-Connell A.
        • Govindarajan G.
        • Habibi J.
        • Hayden M.R.
        • Cooper S.A.
        • Wei Y.
        • Ma L.
        • Qazi M.
        • Link D.
        • Karuparthi P.R.
        • Stump C.
        • Ferrario C.
        • Sowers J.R.
        Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat.
        Am J Physiol Endocrinol Metab. 2007; 293: E355-E363
        • Fulop N.
        • Mason M.M.
        • Dutta K.
        • Wang P.
        • Davidoff A.J.
        • Marchase R.B.
        • Chatham J.C.
        Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart.
        Am J Physiol Cell Physiol. 2007; 292: C1370-C1378
        • Wold L.E.
        • Dutta K.
        • Mason M.M.
        • Ren J.
        • Cala S.E.
        • Schwanke M.L.
        • Davidoff A.J.
        Impaired SERCA function contributes to cardiomyocyte dysfunction in insulin resistant rats.
        J Mol Cell Cardiol. 2005; 39: 297-307
        • Jordan J.E.
        • Simandle S.A.
        • Tulbert C.D.
        • Busija D.W.
        • Miller A.W.
        Fructose-fed rats are protected against ischemia/reperfusion injury.
        J Pharmacol Exp Ther. 2003; 307: 1007-1011
        • Elliott S.S.
        • Keim N.L.
        • Stern J.S.
        • Teff K.
        • Havel P.J.
        Fructose, weight gain, and the insulin resistance syndrome.
        Am J Clin Nutr. 2002; 76: 911-922
        • Rajasekar P.
        • Palanisamy N.
        • Anuradha C.V.
        Increase in nitric oxide and reductions in blood pressure, protein kinase C beta II and oxidative stress by l-carnitine: a study in the fructose-fed hypertensive rat.
        Clin Exp Hypertens. 2007; 29: 517-530
        • Joyeux-Faure M.
        • Rossini E.
        • Ribuot C.
        • Faure P.
        Fructose-fed rat hearts are protected against ischemia-reperfusion injury.
        Exp Biol Med (Maywood). 2006; 231: 456-462
        • Delbosc S.
        • Paizanis E.
        • Magous R.
        • Araiz C.
        • Dimo T.
        • Cristol J.-P.
        • Cros G.
        • Azay J.
        Involvement of oxidative stress and NADPH oxidase activation in the development of cardiovascular complications in a model of insulin resistance, the fructose-fed rat.
        Atherosclerosis. 2005; 179: 43-49
        • Al-Awwadi N.A.
        • Bornet A.
        • Azay J.
        • Araiz C.
        • Delbosc S.
        • Cristol J.-P.
        • Linck N.
        • Cros G.
        • Teissedre P.-L.
        Red wine polyphenols alone or in association with ethanol prevent hypertension, cardiac hypertrophy, and production of reactive oxygen species in the insulin-resistant fructose-fed rat.
        J Agric Food Chem. 2004; 52: 5593-5597
        • Xia Z.
        • Kuo K.-H.
        • Nagareddy P.R.
        • Wang F.
        • Guo Z.
        • Guo T.
        • Jiang J.
        • McNeill J.H.
        N-Acetylcysteine attenuates PKCbeta2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats.
        Cardiovasc Res. 2007; 73: 770-782
        • Matsushima S.
        • Kinugawa S.
        • Ide T.
        • Matsusaka H.
        • Inoue N.
        • Ohta Y.
        • Yokota T.
        • Sunagawa K.
        • Tsutsui H.
        Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart.
        Am J Physiol Heart Circ Physiol. 2006; 291: H2237-H2245
        • Hiranandani N.
        • Bupha-Intr T.
        • Janssen P.M.L.
        SERCA overexpression reduces hydroxyl radical injury in murine myocardium.
        Am J Physiol Heart Circ Physiol. 2006; 291: H3130-H3135
        • Ritchie R.H.
        • Quinn J.M.
        • Cao A.H.
        • Drummond G.R.
        • Kaye D.M.
        • Favaloro J.M.
        • Proietto J.
        • Delbridge L.M.D.
        The antioxidant tempol inhibits cardiac hypertrophy in the insulin-resistant GLUT4-deficient mouse in vivo.
        J Mol Cell Cardiol. 2007; 42: 1119-1128
        • Yaras N.
        • Bilginoglu A.
        • Vassort G.
        • Turan B.
        Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade.
        Am J Physiol Heart Circ Physiol. 2007; 292: H912-H920
        • Sakata S.
        • Lebeche D.
        • Sakata Y.
        • Sakata N.
        • Chemaly E.R.
        • Liang L.F.
        • Padmanabhan P.
        • Konishi N.
        • Takaki M.
        • del Monte F.
        • Hajjar R.J.
        Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer.
        Mol Ther. 2006; 13: 987-996
        • Zhao X.-Y.
        • Hu S.-J.
        • Li J.
        • Mou Y.
        • Chen B.-P.
        • Xia Q.
        Decreased cardiac sarcoplasmic reticulum Ca2+-ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats.
        J Physiol Biochem. 2006; 62: 1-8
        • Pereira L.
        • Matthes J.
        • Schuster I.
        • Valdivia H.H.
        • Herzig S.
        • Richard S.
        • Gomez A.M.
        Mechanisms of Ca2+ i transient decrease in cardiomyopathy of db/db type 2 diabetic mice.
        Diabetes. 2006; 55: 608-615
        • Trost S.U.
        • Belke D.D.
        • Bluhm W.F.
        • Meyer M.
        • Swanson E.
        • Dillmann W.H.
        Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy.
        Diabetes. 2002; 51: 1166-1171
        • Lopaschuk G.D.
        • Tahiliani A.G.
        • Vadlamudi R.V.
        • Katz S.
        • McNeill J.H.
        Cardiac sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic rats.
        Am J Physiol. 1983; 245: H969-H976
        • Li Q.
        • Wu S.
        • Li S.-Y.
        • Lopez F.L.
        • Du M.
        • Kajstura J.
        • Anversa P.
        • Ren J.
        Cardiac-specific overexpression of insulin-like growth factor 1 attenuates aging-associated cardiac diastolic contractile dysfunction and protein damage.
        Am J Physiol Heart Circ Physiol. 2007; 292: H1398-H1403
        • Vasanji Z.
        • Cantor E.J.F.
        • Juric D.
        • Moyen M.
        • Netticadan T.
        Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance.
        Am J Physiol Cell Physiol. 2006; 291: C772-C780
        • Xu S.
        • Ying J.
        • Jiang B.
        • Guo W.
        • Adachi T.
        • Sharov V.
        • Lazar H.
        • Menzoian J.
        • Knyushko T.V.
        • Bigelow D.
        • Schoneich C.
        • Cohen R.A.
        Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging.
        Am J Physiol Heart Circ Physiol. 2006; 290: H2220-H2227
        • Adachi T.
        • Weisbrod R.M.
        • Pimentel D.R.
        • Ying J.
        • Sharov V.S.
        • Schoneich C.
        • Cohen R.A.
        S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide.
        Nat Med. 2004; 10: 1200-1207
        • Kowluru R.A.
        • Engerman R.L.
        • Kern T.S.
        Diabetes-induced metabolic abnormalities in myocardium: effect of antioxidant therapy.
        Free Radic Res. 2000; 32: 67-74
        • Cosenzi A.
        • Bernobich E.
        • Plazzotta N.
        • Seculin P.
        • Odoni G.
        • Bellini G.
        Lacidipine reduces high blood pressure and the target organ damage induced by high fructose diet in rats.
        J Hypertens. 1999; 17: 965-971
        • Iyer S.N.
        • Katovich M.J.
        Effect of acute and chronic losartan treatment on glucose tolerance and insulin sensitivity in fructose-fed rats.
        Am J Hypertens. 1996; 9: 662-668
        • Kamide K.
        • Rakugi H.
        • Higaki J.
        • Okamura A.
        • Nagai M.
        • Moriguchi K.
        • Ohishi M.
        • Satoh N.
        • Tuck M.L.
        • Ogihara T.
        The renin-angiotensin and adrenergic nervous system in cardiac hypertrophy in fructose-fed rats.
        Am J Hypertens. 2002; 15: 66-71
        • Mizushige K.
        • Yao L.
        • Noma T.
        • Kiyomoto H.
        • Yu Y.
        • Hosomi N.
        • Ohmori K.
        • Matsuo H.
        Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model.
        Circulation. 2000; 101: 899-907
        • Kaczmarczyk S.J.
        • Andrikopoulos S.
        • Favaloro J.
        • Domenighetti A.A.
        • Dunn A.
        • Ernst M.
        • Grail D.
        • Fodero-Tavoletti M.
        • Huggins C.E.
        • Delbridge L.M.
        • Zajac J.D.
        • Proietto J.
        Threshold effects of glucose transporter-4 (GLUT4) deficiency on cardiac glucose uptake and development of hypertrophy.
        J Mol Endocrinol. 2003; 31: 449-459
        • Candido R.
        • Forbes J.M.
        • Thomas M.C.
        • Thallas V.
        • Dean R.G.
        • Burns W.C.
        • Tikellis C.
        • Ritchie R.H.
        • Twigg S.M.
        • Cooper M.E.
        • Burrell L.M.
        A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes.
        Circ Res. 2003; 92: 785-792
        • Bendall J.K.
        • Cave A.C.
        • Heymes C.
        • Gall N.
        • Shah A.M.
        Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice.
        Circulation. 2002; 105: 293-296
        • Belke D.D.
        • Larsen T.S.
        • Gibbs E.M.
        • Severson D.L.
        Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice.
        Am J Physiol Endocrinol Metab. 2000; 279: E1104-E1113
        • Finck B.N.
        • Kelly D.P.
        Peroxisome proliferator-activated receptor alpha (PPARalpha) signaling in the gene regulatory control of energy metabolism in the normal and diseased heart.
        J Mol Cell Cardiol. 2002; 34: 1249-1257
        • How O.-J.
        • Aasum E.
        • Severson D.L.
        • Chan W.Y.A.
        • Essop M.F.
        • Larsen T.S.
        Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice.
        Diabetes. 2006; 55: 466-473
        • Rodrigo R.
        • Guichard C.
        • Charles R.
        Clinical pharmacology and therapeutic use of antioxidant vitamins.
        Fundam Clin Pharmacol. 2007; 21: 111-127
        • Macao L.B.
        • Wilhelm Filho D.
        • Pedrosa R.C.
        • Pereira A.
        • Backes P.
        • Torres M.A.
        • Frode T.S.
        Antioxidant therapy attenuates oxidative stress in chronic cardiopathy associated with Chagas’ disease.
        Int J Cardiol. 2007; 123: 43-49
        • Lonn E.
        • Yusuf S.
        • Hoogwerf B.
        • Pogue J.
        • Yi Q.L.
        • Zinman B.
        • Bosch J.
        • Dagenais G.
        • Mann J.F.E.
        • Gerstein H.C.
        • Investigators H.
        Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes—results of the HOPE study and MICRO-HOPE substudy.
        Diabetes Care. 2002; 25: 1919-1927
        • Munzel T.
        • Keaney J.F.
        Are ACE inhibitors a “magic bullet” against oxidative stress?.
        Circulation. 2001; 104: 1571-1574
        • Lara-Padilla E.
        • Kormanovski A.
        • Grave P.A.
        • Olivares-Corichi I.M.
        • Santillan R.M.
        • Hicks J.J.
        Increased antioxidant capacity in healthy volunteers taking a mixture of oral antioxidants versus vitamin C or E supplementation.
        Adv Ther. 2007; 24: 50-59
        • Upston J.M.
        • Witting P.K.
        • Brown A.J.
        • Stocker R.
        • Keaney Jr., J.F.
        Effect of vitamin E on aortic lipid oxidation and intimal proliferation after arterial injury in cholesterol-fed rabbits.
        Free Radic Biol Med. 2001; 31: 1245-1253
        • Wang X.
        • Quinn P.J.
        • Vitamin
        E and its function in membranes.
        Prog Lipid Res. 1999; 38: 309-336
        • Lindholm L.H.
        • Ibsen H.
        • Dahlof B.
        • Devereux R.B.
        • Beevers G.
        • de Faire U.
        • Fyhrquist F.
        • Julius S.
        • Kjeldsen S.E.
        • Kristiansson K.
        • Lederballe-Pedersen O.
        • Nieminen M.S.
        • Omvik P.
        • Oparil S.
        • Wedel H.
        • Aurup P.
        • Edelman J.
        • Snapinn S.
        • grp Ls.
        Cardiovascular morbidity and mortality in patients with diabetes in the Losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
        Lancet. 2002; 359: 1004-1010
        • Goh S.S.C.
        • Woodman O.L.
        • Pepe S.
        • Cao A.H.
        • Qin C.
        • Ritchie R.H.
        The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms.
        Antioxid Redox Signal. 2007; 9: 101-113
        • Hodgson J.M.
        • Watts G.F.
        Can coenzyme Q10 improve vascular function and blood pressure? Potential for effective therapeutic reduction in vascular oxidative stress.
        BioFactors. 2003; 18: 129-136
        • Pirola L.
        • Frojdo S.
        Resveratrol: one molecule, many targets.
        IUBMB Life. 2008; 60: 323-332
        • Hodgson J.M.
        • Watts G.F.
        • Playford D.A.
        • Burke V.
        • Croft K.D.
        Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes.
        Eur J Clin Nutr. 2002; 56: 1137-1142
        • Watts G.F.
        • Playford D.A.
        • Croft K.D.
        • Ward N.C.
        • Mori T.A.
        • Burke V.
        Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus.
        Diabetologia. 2002; 45: 420-426
        • Shephard R.J.
        • Balady G.J.
        Exercise as cardiovascular therapy.
        Circulation. 1999; 99: 963-972
        • Sigal R.J.
        • Kenny G.P.
        • Wasserman D.H.
        • Castaneda-Sceppa C.
        • White R.D.
        Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association.
        Diabetes Care. 2006; 29: 1433-1438
        • Colberg S.R.
        Being active; a commentary.
        Diabetes Educucator. 2007; 33: 989-990
        • Linke A.
        • Adams V.
        • Schulze P.C.
        • Erbs S.
        • Gielen S.
        • Fiehn E.
        • Mobius-Winkler S.
        • Schubert A.
        • Schuler G.
        • Hambrecht R.
        Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle.
        Circulation. 2005; 111: 1763-1770
        • Brassard P.
        • Legault S.
        • Garneau C.
        • Bogaty P.
        • Dumesnil J.-G.
        • Poirier P.
        Normalization of diastolic dysfunction in type 2 diabetics after exercise training.
        Med Sci Sports Exerc. 2007; 39: 1896-1901
        • Fossum E.
        • Gleim G.W.
        • Kjeldsen S.E.
        • Kizer J.R.
        • Julius S.
        • Devereux R.B.
        • Brady W.E.
        • Hille D.A.
        • Lyle P.A.
        • Dahlof B.
        The effect of baseline physical activity on cardiovascular outcomes and new-onset diabetes in patients treated for hypertension and left ventricular hypertrophy: the LIFE study.
        J Intern Med. 2007; 262: 439-448
        • Belardinelli R.
        • Georgiou D.
        • Ginzton L.
        • Cianci G.
        • Purcaro A.
        Effects of moderate exercise training on thallium uptake and contractile response to low-dose dobutamine of dysfunctional myocardium in patients with ischemic cardiomyopathy.
        Circulation. 1998; 97: 553-561
        • Powers S.K.
        • Criswell D.
        • Lawler J.
        • Martin D.
        • Lieu F.K.
        • Ji L.L.
        • Herb R.A.
        Rigorous exercise training increases superoxide dismutase activity in ventricular myocardium.
        Am J Physiol. 1993; 265: 193-201
        • Libonati J.R.
        • Kendrick Z.V.
        • Houser S.R.
        Sprint training improves postischemic, left ventricular diastolic performance.
        J Appl Physiol. 2005; 99: 2121-2127
        • Morris G.S.
        • Baldwin K.M.
        • Lash J.M.
        • Hamlin R.L.
        • Sherman W.M.
        Exercise alters cardiac myosin isozyme distribution in obese Zucker and Wistar rats.
        J Appl Physiol. 1990; 69: 380-383
        • McMullen J.R.
        • Amirahmadi F.
        • Woodcock E.A.
        • Schinke-Braun M.
        • Bouwman R.D.
        • Hewitt K.A.
        • Mollica J.P.
        • Zhang L.
        • Zhang Y.
        • Shioi T.
        • Buerger A.
        • Izumo S.
        • Jay P.Y.
        • Jennings G.L.
        Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy.
        Proc Natl Acad Sci USA. 2007; 104: 612-617