PRECLINICAL RESEARCH: EDITORIAL COMMENT
Metallothionein Reverses the Harmful Effects of Angiotensin II on the Diabetic Heart*
Walmor C. De Mello, MD, PhD*
School of Medicine, Medical Sciences Campus, San Juan, Puerto Rico.
* Reprint requests and correspondence: Dr. Walmor C. De Mello, Department of Pharmacology, School of Medicine, Medical Sciences Campus, UPR, P.O. Box 36-5067, San Juan, Puerto Rico. (Email: wmello{at}rcm.upr.edu).
Key Words: cardiac • remodeling • diabetes • oxidative stress
It is well known that the high incidence of diabetes represents a serious cause of morbidity and mortality in part as the result of cardiovascular complications such as hypertension, coronary artery disease, and stroke (1). Cardiac remodeling, including fibrosis and left ventricular hypertrophy, is found in the diabetic heart (2) as a result of the activation of the renin angiotensin system. The contributing role of angiotensin (Ang) II to diabetic cardiomyopathy has been recognized, a finding supported by the beneficial role of Ang II AT1 receptor blockers and angiotensin-converting enzyme (ACE) inhibitors, which reduce morphologic abnormalities, including myofibrillar remodeling (3). Indeed, the inhibition of the renin angiotensin system has been shown to prevent the generation of atherosclerosis in animal models (1) and the production of cardiac fibrosis, improving impulse propagation with a consequent decrease in the incidence of re-entrant rhythms (4).
Diabetic cardiomyopathy is a clinical condition in which ventricular dysfunction is found in the absence of hypertension and coronary atherosclerosis (5,6). A notable and significant association between diabetes and heart failure in which diastolic dysfunction is the predominant factor has been described (7). Studies performed by Zhou et al. (8) in this issue of the Journal using cardiac-specific metallothionein-overexpressing transgenic mice showed that the harmful effects of Ang II on the diabetic heart, including apoptosis, fibrosis, and nitrosative lesions, are greatly reversed by metallothionein—a cysteine-related protein able to scavenge free radicals, including superoxide and peroxynitrite (9). The authors of several studies associate diabetes with zinc deficiency and discuss the possibility that zinc induces metallothionein synthesis in animals and humans (10). Moreover, the possible relationship between zinc deficiency and heart failure has been recently re-evaluated (11), taking into consideration that ACE and matrix metalloproteinases are zinc enzymes that play a role on cardiac remodeling. Moreover, thiazide diuretics, which are frequently used in patients with heart failure and hypertension, cause zincuria and a decrease in tissue levels of zinc (11).
The fundamental mechanism involved in the beneficial effect of metallothionein is the decrease of oxidative stress. It is known that Ang II stimulates superoxide production via the AT1 receptor by activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is localized in many tissues, including vascular smooth muscle cells, fibroblasts, and heart tissue (12). Indeed, enhanced levels of Ang II found in different pathophysiologic conditions such as hypertension and heart failure cause increased superoxide production concurrently with a decrease in nitric oxide activity (13–15). Angiotensin II induces activation of NADPH oxidase, enhances the expression of NADPH subunits, and stimulates reactive oxygen species production in vascular smooth muscle in vitro as well as in intact arteries (16,17). Although different possible mechanisms are involved in the prevention of Ang II–mediated cardiac damage in diabetes, the work of Zhou et al. (8) presents evidence that metallothionein suppresses NOX p47phox activation as well as oxidative and nitrosactive damage. It is known that the beneficial effects of AT1 blockers and ACE inhibitors in diabetic cardiomyopathy are in part related to the increased availability of nitric oxide (18), a view supported by the finding that the use of olmesartan decreased oxidative stress and hypoxia-induced left ventricular remodeling in part through inhibition of nuclear factor-kappa B and matrix methalloproteinase-9 activities (19). In patients with essential hypertension, for instance, the use of valsartan reduced QTc dispersion—an effect probably related to its antioxidative stress effect (20), whereas in age-dependent cardiomyopathy found in ACE-2-null mice, the increased level of Ang II mediated the oxidative stress and the neutrophilic infiltration (21).
Antioxidants have a potential value in the treatment of several cardiovascular diseases involving oxidative stress (22,23). Large clinical trials such as CHAOS (Cambridge Heart Oxidant Study) (24) and ASAP (Anti-oxidant Supplementation in Atherosclerosis Prevention) study (25) showed positive results, whereas other trials were not as convincing (26). Nitrosactive and oxidative changes of proteins can modify enzyme functions and protein localization, and different enzymes involved in the generation of reactive oxygen species are located in different subcellular compartments (27) and exert different functions. Because an ideal antioxidant should be able to remove a nitro group from an altered protein without generating any other effect (28), it is difficult to achieve this goal and to analyze its beneficial effect for human beings. This justifies the continuous effort to increase our knowledge in this important area of cell biology and pathology.
The implications of these findings for cardiology are many. It is known, for instance, that the infarct sizes in patients with diabetes-associated hyperglycemia are much larger than those in nondiabetic patients (29), which indicate that stress hyperglycemia enhances the sensitivity of cardiac muscle to injury. Moreover, an association between oxidative stress and atrial fibrillation has been described (30). The work of Zhou et al. (8) improves our knowledge of how to reduce the cardiac damage elicited by diabetes in animals by reversing the oxidative stress caused by Ang II and opens the possibility of using antioxidants for the prevention of cardiac damage in diabetic patients.
Certainly, additional clinical studies as well as the use of clinical markers and the determination of end points are necessary to translate these pre-clinical studies and provide good management for diabetic patients with a clear risk of cardiomyopathy. For instance, thioredoxin, which is a redox-acting protein and considered to be a biomarker for several cardiovascular diseases associated with oxidative stress, is useful for diabetic patients with risk of cardiomyopathy (31), and the same seems to be true for homocysteine, which is considered an important source of oxidative stress in cardiomyopathy (31). Because there is a synergism between hyperglycemia and inflammation, the use of inflammatory markers such as monocyte chemoattractant protein-1 and the von Willebrand factor is also useful (32). In the case of atrial fibrillation, which has been associated with myocardial oxidative stress, the use of serum markers of oxidation and inflammation can be useful. Indeed, a recent study (30) supports the view that oxidative stress markers such as derivatives of reactive oxidative metabolites and ratios of oxidized to reduced glutathione as well as cysteine are useful in patients with persistent atrial fibrillation. Although there is evidence that dietary supplementation with vitamin E improves heart failure in human type 1 diabetic cardiomyopathy through the suppression of oxidized glutathione and 8-iso prostaglandin F2-alpha (33), the causes of diabetic cardiomyopathy remain elusive (34). Indeed, epidemiological studies have indicated structural abnormalities in the left ventricle before the evidence of clinical diabetes (34). Further translational studies on metabolic, functional, and structural changes in the diabetic heart will help to clarify the etiology of diabetic cardiomyopathy.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Cooper ME. The role of the renin angiotensin aldosterone system in diabetes and its vascular complications Am J Hypertens 2004;17:16S-20S.[Web of Science][Medline]2. Chen S, Evans T, Mukherjee K, Karmazyn M, Chakrabarti S. Diabetes-induced myocardial structural changes: role of endothelin-1 and its receptors J Mol Cell Cardiol 2000;32:1621-1629.[CrossRef][Web of Science][Medline] 3. Machackova J, Liu X, Lukas A, Dhalla NS. Renin-angiotensin blockade attenuates cardiac myofibrillar remodeling in chronic diabetes Mol Cell Biochem 2004;261:271-278.[CrossRef][Web of Science][Medline] 4. De Mello WC. Impaired cell communication in the diabetic heart. The role of the renin angiotensin system. Mol Cell Biochem 2007;296:53-58.[CrossRef][Web of Science][Medline] 5. Picano E. Diabetic cardiomyopathy. The importance of being earliest. J Am Coll Cardiol 2003;42:454-457.[Free Full Text] 6. Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review Mol Cell Biochem 2004;261:187-191.[CrossRef][Web of Science][Medline] 7. McMurray JJ, Stewart S. Epidemiology, etiology and prognosis of heart failure Heart 2000;83:596-602.[Free Full Text] 8. Zhou G, Li X, Hein DW, et al. Metallothionein suppresses angiotensin II–induced nicotinamide adenine dinucleotide phosphate oxidase activation, nitrosative stress, apoptosis, and pathological remodeling in the diabetic heart J Am Coll Cardiol 2008;52:655-666.[Abstract/Free Full Text] 9. Cai L, Klein JB, Kang XJ. Metallothionein inhibits peroxynitrite-induced DNA and lipoprotein damage J Biol Chem 2000;275:38957-38960.[Abstract/Free Full Text] 10. Isman MS, Loots du T. Diabetes, metallothionein and zinc interaction: a review Biofactors 2007;29:203-212.[Web of Science][Medline] 11. Cohen N, Golik A. Zinc balance and medications commonly used in the management of heart failure Heart Fail Rev 2006;11:19-24.[CrossRef][Web of Science][Medline] 12. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase. Role in cardiovascular biology and disease. Circ Res 2000;86:494-501.[Abstract/Free Full Text] 13. Lauersen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG. Role of superoxide in angiotensin II-induced but not catechol-induced hypertension Circulation 1997;95:588-593.[Abstract/Free Full Text] 14. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased accumulation of tissue ACE in human atherosclerotic coronary disease Circulation 1996;94:2756-2767.[Abstract/Free Full Text] 15. Hornig B, Landmesser U, Kohler C, et al. Comparative effects of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase Circulation 2001;103:799-805.[Abstract/Free Full Text] 16. Cruzado MC, Risler NR, Miatello RM, Yao G, Schiffrin EL, Touyz RM. Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: effect of Ang II and role of insulin like growth factor-1 receptor transactivation Am J Hypertens 2005;18:81-87.[CrossRef][Web of Science][Medline] 17. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells Circ Res 1994;74:1141-1148.[Abstract/Free Full Text] 18. Kamik AA, Fields AV, Shannon RP. Diabetic cardiomyopathy Curr Hypertens Rep 2007;9:467-473.[CrossRef][Web of Science][Medline] 19. Yamashita C, Hayahi T, Mori T, et al. Angiotensin II receptor blocker reduces oxidative stress and attenuates hypoxia-induced left ventricular remodeling in apolipoprotein E-knockout mice Hypertens Res 2007;30:1219-1230.[CrossRef][Web of Science][Medline] 20. Miyajima K, Minatogushi S, Ito Y, et al. Reduction of QTc dispersion by the angiotensin II receptor blocker valsartan may be related to its anti-oxidative stress effect in patients with essential hypertension Hypertens Res 2007;30:307-313.[CrossRef][Web of Science][Medline] 21. Outdit GY, Kassiri Z, Patel MP, et al. Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice Cardiovasc Res 2007;75:29-39.[Abstract/Free Full Text] 22. Digiesi D, Lenuzza M, Digiese G. Prospects for the use of antioxidant therapy in hypertension Ann Ital Med Int 2001;16:93-100.[Medline] 23. Duffy SJ, Gokce N, Holbrook M, et al. Treatment of hypertension with ascorbic acid Lancet 1999;354:2048-2049.[CrossRef][Web of Science][Medline] 24. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) Lancet 1996;347:781-786.[CrossRef][Web of Science][Medline] 25. Salonen RM, Nyyssonen K, Kaikkomen J. Six year effect of vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention. (ASAP)Study. Circulation 2003;107:947-953.[Abstract/Free Full Text] 26. GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell"ínfarto miocardico. Lancet 1999;354:447-455.[CrossRef][Web of Science][Medline] 27. Hilenski LL, Clempus RE, Quinn MT, et al. Distinct subcellular localizations of Nox1 and No4 in vascular smooth muscle cells Atheroscler Tromb Vac Biol 2004;24:677-683. 28. Harrisdon DG, Dilakov S. Oxidative events in cell and vascular biologyIn: Re R, DiPette DJ, Schiffrin EL, Sowers JR, editors. Molecular Mechanisms in Hypertension. New York, NY: Taylor and Francis; 2006. pp. 297-320. 29. Webster KA. Stress hyperglycemia and enhanced sensitivity to myocardial infarction Curr Hypertens Rep 2008;10:78-84.[CrossRef][Web of Science][Medline] 30. Neuman RB, Bloom HL, Shukrullah I, et al. Oxidative stress markers are associated with persistent atrial fibrillation Clin Chem 2007;53:1652-1657.[Abstract/Free Full Text] 31. Hoshino Y, Shioji K, Nakamura H, Yodoi J. From oxygen sensing to heart failure: role of thioredoxin Antioxid Redox Signal 2007;9:689-699.[CrossRef][Web of Science][Medline] 32. Ray KK, Cannon CP, Morrow DA, et al. Synergistic relationship between hyperglycemia and inflammation with respect to clinical outcomes in non-ST-elevation coronary syndromes: analysis from OPUS-TIMI 16 and TACTICS-TIMI 18 Eur Heart J 2007;28:806-813.[Abstract/Free Full Text] 33. Hamblin M, Smith HM, Hill MF. Dietary supplementation with vitamin E ameliorates cardiac failure in type 1 diabetic cardiomyopathy by suppressing myocardial generation of 8-iso prostaglandin F2alpha and oxidized glutathione Card Fail 2007;13:884-892.[CrossRef] 34. Guha A, Harmancey R, Taegtmeyer H. Nonischemic heart failure in diabetes mellitus Curr Opin Cardiol 2008;23:241-248.[CrossRef][Web of Science][Medline]
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