Abstract
Oxidative stress is considered to play an important role in the pathogenesis of diabetes-induced cardiovascular disease (CVD), which is invariably associated with abnormal blood lipid profile, insulin resistance and metabolic syndrome. Stress, smoking, high saturated fat intake as well as low fruit and vegetable intakes have been shown to increase oxidative stress and hyperlipidemia, which increase the predisposition of diabetic subjects to atherosclerosis, stroke and coronary heart disease. The oxidation of low-density lipoprotein by oxidative stress is essential for the development of atherosclerosis, and the reduction in oxidative stress as well as blood glucose and cholesterol is considered critical for the prevention of diabetes-induced CVD. Although epidemiological studies have demonstrated that vitamin C and vitamin E decrease the incidence of coronary heart disease, different clinical trials have failed to support the beneficial effect of these antioxidants. Nonetheless, it has been suggested that natural forms of these vitamins may be more efficacious than synthetic vitamins, and this may explain the inconsistencies in results. Antioxidants, N-acetyl-l-cysteine and resveratrol, have also been shown to attenuate the diabetes-induced cardiovascular complications. It has been indicated that the antioxidant therapy may be effective in a prevention strategy rather than as a treatment for CVD. The evidence presented here supports the view that cardiovascular complications in diabetes may be induced by oxidative stress and appropriate antioxidant therapy may be promising for attenuating the progression of diabetes-induced CVD.
Similar content being viewed by others
References
Regan TJ (1983) Congestive heart failure in the diabetic. Annu Rev Med 34:161–168
Dhalla NS, Pierce GN, Innes GN, Beamish RE (1985) Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol 1:263–281
Schaffer SW (1991) Cardiomyopathy associated with non-insulin-dependent diabetes. Mol Cell Biochem 107:1–20
Dhalla NS, Lui X, Panagia V, Takeda N (1998) Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res 40:239–247
Dhalla NS, Rangi S, Zieroth S, Xu Y-J (2012) Alterations in sarcoplasmic reticulum and mitochondrial functions in diabetic cardiomyopathy. Exptl Clin Cardiol 17:115–120
Ceriello A, Motz E (2004) Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24:816–823
Chen AF, Chen DD, Daiber A, Faraci FM, Li H, Rembold CM, Laher I (2012) Free radical biology of the cardiovascular system. Clin Sci 123:73–91
Roberts C, Sindhu KK (2009) Oxidative stress and metabolic syndrome. Life Sci 84:705–712
Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18:655–673
Tappia PS, Dent MR, Dhalla NS (2006) Oxidative stress and redox regulation of phospholipase D in myocardial disease. Free Rad Bio Med 41:349–361
Das DK (2001) Redox regulation of cardiomyocyte survival and death. Antioxid Redox Signal 3:23–37
Herrlich P, Bohmer FD (2000) Redox regulation of signal transduction in mammalian cells. Biochem Pharmacol 59:35–41
Adameova A, Xu YJ, Duhamel TA, Tappia PS, Shan L, Dhalla NS (2009) Anti-atherosclerotic molecules targeting oxidative stress and inflammation. Curr Pharm Des 15:3094–3107
Makazan Z, Saini HK, Dhalla NS (2007) Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts. Am J Physiol 292:1986–1994
Xu YJ, Zhang M, Ji L, Elimban V, Chen L, Dhalla NS (2012) Suppression of high lipid diet induced atherosclerosis by sarpogrelate. J Mol Cell Med 16:2394–2400
Kanter JE, Bornfeldt KE (2012) Inflammation and diabetes-accelerated atherosclerosis: myeloid cell mediators. Trend Endocrinol Metab. doi:10.1016/j.tem.2012.10.002
Bell DSH, Face MB (2003) Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diab Care 26:2433–2441
Hadi N, Yousif NG, Al-Amran FG, Huntei NK, Mohammad BI, Ali SJ (2012) Vitamin E and telmisartan attenuates doxorubicin induced cardiac injury in rat through down regulation of inflammatory response. BMC Cardiovasc Disord 12:63
Steinberg D (1993) Antioxidant vitamins and coronary heart disease. N Eng J Med 328:1487–1489
Tappia PS, Thliveris J, Xu YJ, Aroutiounova N, Dhalla NS (2011) Effects of amino acid supplementation on myocardial cell damage and cardiac function in diabetes. Exp Clin Cardiol 16:e17–e22
Jain SK, McVie R (1999) Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and type 1 diabetic patients. Diabetes 49:1850–1855
De Mattia G, Bravi MC, Laurenti O, Cassone-Faldetta M, De Luca O, Armiento A, Ferri C (1998) Reduction of oxidative stress by oral N-acetyl-l-cysteine treatment decreases plasma soluble vascular cell adhesion molecule-1 concentrations in non-obese, non-dyslipidaemic, normotensive, patients with non-insulin-dependent diabetes. Diabetologia 41:1392–1396
Gonzalez-Ordonez AJ, Fernandea-Carreira JM, Fernandez-Alvarez CR, Obaya RV, Macias-Robles MD, Gonzalez-Franco A, Garcia MAA (2003) The concentration of soluble vascular cell adhesion molecule-1 and lipids are independent associated with venous thromboembolism. Thrombosis 88:1035–1043
Wu CH, Huang SM, Yen GC (2011) Silymarin: a novel antioxidant with antiglycation and antiinflammatory properties in vitro and in vivo. Antioxid Redox Signal 14:353–366
Cai W, Torreggiani M, Zhu L, Chen X, He JC, Striker GE, Vlassara H (2009) AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-δ: implications for vascular disease. Am J Physiol 298:C624–C634
Cai W, He JC, Zhu L, Peppa M, Lu C, Uribarri J, Vlassara H (2004) High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation 110:285–291
Gibson KR, Winterburn TJ, Barrett F, Sharma S, MacRyry SM, Megson IL (2011) Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes. Cardiovasc Diabetol 10:43–50
Xu YJ, Aziz OA, Bhugra P, Arneja AS, Mendia MR, Dhalla NS (2003) Potential role of lysophosphatidic acid in hypertension and atherosclerosis. Can J Cardiol 19:1525–1536
Neri S, Signorelli SS, Torrisi B, Pulvrenti D, Mauceri B, Abate G, Ignaccolo L, Bordonaro F, Cilio D, Calvagno S, Leotta C (2005) Effects of antioxidant supplementation on postprandial oxidative stress and endothelial dysfunction: a single-blind, 15-day clinical trial in patients with untreated type-2 diabetes, subjects with impaired glucose tolerance, and healthy controls. Clin Ther 27:1764–1773
Marian AJ (2009) Experimental therapies in hypertrophic cardiomyopathy. J Cardiovasc Transl Res 2:483–492
Koramaz I, Pulathan Z, Usta S, Karahan C, Alver A, Yaris E, Kalyoncu NI (2006) Cardioprotective effect of cold-blood cardioplegia enriched with N-acetylcysteine during coronary artery bypass grafting. Ann Thorac Surg 81:613–618
Rodrigues AJ, Evora PR, Bassetto S, Alves L Jr, Scorzoni FA, Origuela EA, Vicente WV (2009) Blood cardioplegia with N-acetylcysteine may reduce coronary endothelial activation and myocardial oxidative stress. Heart Surg Forum 12:E44–E48
Prabhu A, Sujatha DI, Kanagarajan N, Vijayalakshmi MA, Ninan B (2009) Effect of N-acetylcysteine in attenuating ischemic reperfusion injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Ann Vasc Surg 23:645–651
Tossios P, Bloch W, Huebner A, Raji MR, Dodos F, Klass O, Suedkamp M, Kasper SM, Hellmich M, Mehlhorn U (2003) N-acetylcysteine prevents reactive oxygen species-mediated myocardial stress in patients undergoing cardiac surgery: results of a randomized, double-blind, placebo-controlled clinical trial. J Thorac Cardiovas Surg 126:1513–1520
Horowitz JD, Henry CA, Syrjanen ML, Louis WJ, Fish RD, Smith TW, Antman EM (1988) Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 77:787–794
Rosenblat M, Volkova N, Aviram M (2012) Pomegranate phytosterol (β-sitosterol) and polyphenolic antioxidant (punicalagin) addition to statin, significantly protected against macrophage foam cells formation. Atherosclerosis. doi:10.1016/j.atherosclerosis.2012.10.054
Sparrow CP, Doebber TW, Olszewski J, Wu MS, Ventre J, Stevens KA, Chao YS (1992) Low density lipoprotein is protected from oxidation and progression in rabbits by the antioxidant N, N′-diphenyl-phenylenediamine. J Clin Invest 89:1885–1891
Jha P, Flather M, Lonn E, Farkouh M, Yusuf S (1995) The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic and clinical trial data. Ann Intern Med 123:860–872
Steinberg D, Participants W (1992) Antioxidants in the prevention of human atherosclerosis. Circulation 85:2338–2344
Waters DD, Alderman EL, Hsia J, Howard BV, Cobb FR, Rogers WJ, Ouyang P, Thompson P, Tardif JC, Higgison L, Bittner V, Steffes M, Gordon DJ, Proschan M, Younes N, Verter JI (2002) Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA 288:2432–2440
Steinhubal SR (2008) Why have antioxidants failed in clinical trials? Am J Cardiol 102(suppl):14D–19D
Dorr RT (1996) Cytoprotective agents for anthracyclines. Semin Oncol 23:23–24
Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with Doxorubicin. Cancer 97:2869–2879
Wattanapitayakul SK, Chularojmontri L, Herunsalee A, Charuchongkolwongse S, Niumsakul S, Bauer JA (2005) Screening of antioxidants from medicinal plants for cardioprotective effect against doxorubicin toxicity. Basic Clin Pharmacol Toxicol 96:80–87
Chularojmontri L, Wattanapitayakul SK, Herunsalee A, Charuchongkolwongse S, Niumsakul S, Srichairat S (2005) Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity. Biol Pharm Bull 28:1165–1171
van Dalen EC, Caron HN, Dickinson HO, Kremer LCM (2011) Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 15:CD003917
Smoliga JM, Baur JA, Hausenblas HA (2011) Resveratrol and health—a comprehensive review of human clinical trials. Mol Nutr Food Res 55:1129–1141
Saini H, Dhami P, Xu YJ, Cheema S, Arneja A, Dhalla NS (2006) Modification of biochemical and cellular processes in the development of atherosclerosis by red wine. In: Cheema SK (ed) Biochemistry of atherosclerosis. Springer Science +Business Media, LLC., New York, pp 475–494
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, Couteur DL, Shaw RJ, Navas P, Puigserver P, Ingram DK, Cabo RD, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342
Ku CR, Lee HJ, Kim SK, Lee EY, Lee MK, Lee EJ (2012) Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic ß-cell and the cleavage of poly(ADP-ribose) polymerase. Endocr J 59:103–109
Matos RS, Baroncini LA, Precoma LB, Winter G, Lambach PH, Caron EY, Kaiber F, Precoma DB (2012) Resveratrol causes antiatherogenic effects in an animal model of atherosclerosis. Arq Bras Cardiol 98:136–142
Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Discov 5:493–506
Zghonda N, Yoshida S, Araki M, Kusunoki M, Mliki A, Ghorbel A, Miyazaki H (2011) Greater effectiveness of ε-viniferin in red wine than its monomer resveratrol for inhibiting vascular smooth muscle cell proliferation and migration. Biosci Biotechnol Biochem 75:1259–1267
Marchal J, Blanc S, Epelbaum J, Aujard F, Pifferi F (2012) Effects of chronic restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate Microcebus Murinus. PLoS ONE 7:e34289
Turan B, Tuncay E, Vassort G (2012) Resveratrol and diabetic cardiac function: focus on recent in vitro and in vivo studies. J Bioenerg Biomemb 44:281–296
Duhamel TA, Xu YJ, Arneja AS, Dhalla NS (2007) Targeting platelets for prevention and treatment of cardiovascular disease. Expert Opin Ther Targ 11:1523–1533
Malinowska J, Olas B (2011) Response of blood platelets to resveratrol during a model of hyperhomocysteinemia. Platelets 22:277–283
Esker S, Banerjee A, Simone TM, Gallati CA, Mousa SA (2009) Resveratrol as a supplemental therapeutic in cardiovascular and metabolic syndromes: a critical review. Curr Nut Food Sci 5:1–8
Stef G, Csiszar A, Lerea K, Ungvari Z, Veress G (2006) Resveratrol inhibits aggregation of platelets from high-risk cardiac patients with aspirin resistance. J Cardiovasc Pharmacol 48:1–5
Chang HC, Chen TC, Tai YT, Chen TL, Chiu WT, Chen RM (2011) Resveratrol attenuates oxidized LDL-evoked lox-2 signaling and consequently protects against apoptotic insults to cerebrovascular endothelial cells. J Cereb Blood Flow Metab 31:842–854
Robich MP, Osipov RM, Nezafat R, Feng J, Clements RT, Bianchi C, Boodhwani M, Coady MA, Laham RJ, Sellke FW (2010) Myocardial protection, perioperative management, and vascular biology. Circulation 122:S142–S149
Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, Nishikawa M, Iwasaka T, Das DK (2011) Modified resveratrol longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Nutr Res 31:842–847
Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth K, Szabados E (2012) Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemotheol Microcirc 50:179–187
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
Lu R, Serrero G (1999) Resveratrol, a natural product derived from grape inhibits the growth of human breast cancer cells. J Cell Physiol 179:297–304
Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CWW, Fong HHS, Farnsworth NR, Kinghorn D, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220
Kaneko H, Anzai T, Morisawa M, Kohno T, Nagai T, Anzai A, Takahashi T, Shimoda M, Sasaki A, Maekawa Y, Yoshimura K, Aoki H, Tsubota K, Yoshikawa T, Okada Y, Ogawa S, Fukuda K (2011) Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization. Atherosclerosis 217:350–357
Diaz MN, Frei B, Vita JA, Keaney JF (1997) Antioxidants and atherosclerotic heart disease. New Eng J Med 337:408–416
Voloshyna I, Hussaini SM, Reiss AB (2012) Resveratrol in cholesterol metabolism and atherosclerosis. J Med Food 15:763–773
Chong ZZ, Shang YC, Wang S, Maiese K (2011) SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin 16:167–178
Das S, Santani DD, Dhalla NS (2007) Experimental evidence for cardioprotective effects of red wine. Exp Clin Cardiol 12:5–10
Riccioni G, D’Orazio N, Salvatore C, Franceschelli S, Pesce M, Speranza L (2012) Carotenoids and vitamins C and E in the prevention of cardiovascular disease. Int J Vit Nutr Res 82:15–16
Will JC, Ford ES, Browman BA (1999) Serum vitamin C concentration and diabetes: finding from the third national health and nutrition examination surveys 1988–1994. Am J Nutr 70:49–52
Tome-Carneiro J, Gonzalvez M, Larrosa M, Yanez-Gascon MJ, Garcia-Almagro FJ, Ruiz-Ros JA, Garcia-Conesa MT, Tomas-Babberan FA, Espin JC (2012) One –year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol 110:356–363
Bhatt JK, Thomas S, Nanjan MJ (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 32:537–541
Dakhale GN, Chaudhari HV, Shrivastava M (2011) Supplementation of vitamin C reduced blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. Adv Pharmacol Sci. doi:10.1155/2011/195271
Mazloom Z, Hejazi N, Dabbaghmanesh MH, Tabatabaei HR, Ahmadi A, Ansar H (2011) Effect of vitamin C supplementation on postprandial oxidative stress and lipid profile in type 2 diabetic patients. Pak L Biol Sci 14:900–904
Illison VK, Rondo PH, de Olivera AM, D’Abronzo FH, Campos KF (2011) The relationship between plasma α-tocopherol concentration and vitamin E intake in patients with type 2 diabetes mellitus. Int J Vit Nutr Res 81:12–20
Shab-Bidar S, Mazloum Z, Mousavi-Shirazifard Z (2012) Daily vitamin E supplement do not improve metabolic and glycemic control in type 2 diabetic patients: a double blinded randomized controlled trial. J Diabetes. doi:10.1111/j.1753-0407.2012
Treweeke AT, Winterburn TJ, Mackenzie I, Barrett F, Barr C, Rushworth GF, Dransfield I, Macrury SM, Megson IL (2012) N-acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomized controlled trial. Diabetologia. doi:10.1007/s00125-012-2685-z
Acknowledgments
Infrastructural support for this project was provided by St. Boniface Hospital Research Foundation. Dr. N. S. Neki was a visiting professor from Department of Internal Medicine, Government Medical College, Amritsar, India.
Conflict of interest
None of the authors have any conflict of interest with any granting agency.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xu, YJ., Tappia, P.S., Neki, N.S. et al. Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants. Heart Fail Rev 19, 113–121 (2014). https://doi.org/10.1007/s10741-013-9379-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10741-013-9379-6