Abstract
Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multifactorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling.
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References and Recommended Reading
Ide T, Tsutsui H, Kinugawa S, et al.: Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circ Res 2000, 86:152–157.
Date M, Morita T, Yamashita N, et al.: The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model. J Am Coll Cardiol 2002, 39:907–912.
Giordano FJ: Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005, 115:500–508.
Matsushima S, Ide T, Yamato M, et al.: Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 2006, 113:1779–1786.
van Empel VPM, Bertrand AT, van der Nagel R, et al.: Downregulation of apoptosis-inducing factor in harlequin mutant mice sensitizes the myocardium to oxidative stress-related cell death and pressure overload-induced decompensation. Circ Res 2005, 96:e92–e101.
Ide T, Tsutsui H, Hayashidani S, et al.: Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res 2001, 88:529–535.
Ikeuchi M, Matsusaka H, Kang D, et al.: Overexpression of mitochondrial transcription factor A ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation 2005, 112:683–690.
Berry CE, Hare JM: Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol (Lond) 2004, 555:589–606.
Farquharson CAJ, Butler R, Hill A, et al.: Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002, 106:221–226.
Engberding N, Spiekermann S, Schaefer A, et al.: Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug? Circulation 2004, 110:2175–2179.
Stull LB, Leppo MK, Szweda L, et al.: Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy. Circ Res 2004, 95:1005–1011.
Minhas KM, Saraiva RM, Schuleri KH, et al.: Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. Circ Res 2006, 98:271–279.
Shah AM: Divergent roles of endothelial nitric oxide synthase in cardiac hypertrophy and chamber dilatation? Cardiovasc Res 2005, 66:421–422.
Ichinose F, Bloch KD, Wu JC, et al.: Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. Am J Physiol Heart Circ Physiol 2004, 286:H1070–H1075.
Scherrer-Crosbie M, Ullrich R, Bloch KD, et al.: Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 2001, 104:1286–1291.
Ruetten H, Dimmeler S, Gehring D, et al.: Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload. Cardiovasc Res 2005, 66:444–453.
Dawson D, Lygate CA, Zhang MH, et al.: nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation 2005, 112:3729–3737.
Saraiva RM, Minhas KM, Raju SVY, et al.: Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: role of nitroso-redox equilibrium. Circulation 2005, 112:3415–3422.
Takimoto E, Champion HC, Li M, et al.: Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 2005, 115:1221–1231.
Liu YH, Carretero OA, Cingolani OH, et al.: Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 2005, 289:H2616–H2623.
Cave AC, Brewer AC, Narayanapanicker A, et al.: NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006, 8:691–728.
Geiszt M: NADPH oxidases: new kids on the block. Cardiovasc Res 2006, 71:289–299.
Li JM, Shah AM: Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004, 287:R1014–R1030.
Li JM, Gall NP, Grieve DJ, et al.: Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. Hypertension 2002, 40:477–484.
Fukui T, Yoshiyama M, Hanatani A, et al.: Expression of p22-phox and gp91-phox, essential components of NADPH oxidase, increases after myocardial infarction. Biochem Biophys Res Commun 2001, 281:1200–1206.
Krijnen PAJ, Meischl C, Hack CE, et al.: Increased Nox2 expression in human cardiomyocytes after acute myocardial infarction. J Clin Pathol 2003, 56:194–199.
Kobayashi N, Yoshida K, Nakano S, et al.: Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. Hypertension 2006, 47:671–679.
Heymes C, Bendall JK, Ratajczak P, et al.: Increased myocardial NADPH oxidase activity in human heart failure 3. J Am Coll Cardiol 2003, 41:2164–2171.
Maack C, Kartes T, Kilter H, et al.: Oxygen free radical release in human failing myocardium is associated with increased activity of Rac1-GTPase and represents a target for statin treatment. Circulation 2003, 108:1567–1574.
Kim YM, Guzik TJ, Zhang YH, et al.: A myocardial Nox2 containing NAD(P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 2005, 97:629–636.
Dudley SC Jr, Hoch NE, McCann LA, et al.: Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases. Circulation 2005, 112:1266–1273.
Bendall JK, Cave AC, Heymes C, et al.: Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II—induced cardiac hypertrophy in mice. Circulation 2002, 105:293–296.
Nakagami H, Takemoto M, Liao JK: NADPH oxidase-derived superoxide anion mediates angiotensin II—induced cardiac hypertrophy. J Mol Cell Cardiol 2003, 35:851–859.
Satoh M, Ogita H, Takeshita K, et al.: Requirement of Rac1 in the development of cardiac hypertrophy. PNAS 2006, 103:7432–7437.
Byrne JA, Grieve DJ, Bendall JK, et al.: Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II—induced cardiac hypertrophy. Circ Res 2003, 93:802–805.
Maytin M, Siwik DA, Ito M, et al.: Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox. Circulation 2004, 109:1168–1171.
Johar S, Cave AC, Narayanapanicker A, et al.: Aldosterone mediates angiotensin II—induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J 2006, 20:1546–1548.
Touyz RM, Mercure C, He Y, et al.: Angiotensin II—dependent chronic hypertension and cardiac hypertrophy are unaffected by gp91phox-containing NADPH oxidase. Hypertension 2005, 45:530–537.
Grieve DJ, Byrne JA, Siva A, et al.: Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload. J Am Coll Cardiol 2006, 47 817–826.
Cox MJ, Hawkins UA, Hoit BD, et al.: Attenuation of oxidative stress and remodeling by cardiac inhibitor of metalloproteinase protein transfer. Circulation 2004, 109:2123–2128.
Zhao W, Ahokas RA, Weber KT, et al.: ANG II—induced cardiac molecular and cellular events: role of aldosterone. Am J Physiol Heart Circ Physiol 2006, 291:H336–H343.
Rude MK, Duhaney TA, Kuster GM, et al.: Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension 2005, 46:555–561.
Zhang M, Kho AL, Anilkumar N, et al.: Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)—containing NADPH oxidase. Circulation 2006, 113:1235–1243.
Cucoranu I, Clempus R, Dikalova A, et al.: NAD(P)H oxidase 4 mediates transforming growth factor-ta1—induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 2005, 97:900–907.
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Zhang, M., Shah, A.M. Role of reactive oxygen species in myocardial remodeling. Curr Heart Fail Rep 4, 26–30 (2007). https://doi.org/10.1007/s11897-007-0022-5
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DOI: https://doi.org/10.1007/s11897-007-0022-5