Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2010 Feb 27

PMID 20185797

Citations 273

Authors

Tetsuro Ago

Junya Kuroda

Jayashree Pain

Cexiong Fu

Hong Li

Junichi Sadoshima

Affiliations

Soon will be listed here.

Abstract

Rationale: NADPH oxidases are a major source of superoxide (O(2)(-)) in the cardiovascular system. The function of Nox4, a member of the Nox family of NADPH oxidases, in the heart is poorly understood.

Objective: The goal of this study was to elucidate the role of Nox4 in mediating oxidative stress and growth/death in the heart.

Methods And Results: Expression of Nox4 in the heart was increased in response to hypertrophic stimuli and aging. Neither transgenic mice with cardiac specific overexpression of Nox4 (Tg-Nox4) nor those with catalytically inactive Nox4 (Tg-Nox4-P437H) showed an obvious baseline cardiac phenotype at young ages. Tg-Nox4 gradually displayed decreased left ventricular (LV) function with enhanced O(2)(-) production in the heart, which was accompanied by increased apoptosis and fibrosis at 13 to 14 months of age. On the other hand, the level of oxidative stress was attenuated in Tg-Nox4-P437H. Although the size of cardiac myocytes was significantly greater in Tg-Nox4 than in nontransgenic, the LV weight/tibial length was not significantly altered in Tg-Nox4 mice. Overexpression of Nox4 in cultured cardiac myocytes induced apoptotic cell death but not hypertrophy. Nox4 is primarily localized in mitochondria and upregulation of Nox4 enhanced both rotenone- and diphenyleneiodonium-sensitive O(2)(-) production in mitochondria. Cysteine residues in mitochondrial proteins, including aconitase and NADH dehydrogenases, were oxidized and their activities decreased in Tg-Nox4.

Conclusions: Upregulation of Nox4 by hypertrophic stimuli and aging induces oxidative stress, apoptosis and LV dysfunction, in part because of mitochondrial insufficiency caused by increased O(2)(-) production and consequent cysteine oxidation in mitochondrial proteins.

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References

Mahadev K, Motoshima H, Wu X, Ruddy J, Arnold R, Cheng G . The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol. 2004; 24(5):1844-54. PMC: 350558. DOI: 10.1128/MCB.24.5.1844-1854.2004. View

Krause K . Aging: a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol. 2006; 42(4):256-62. DOI: 10.1016/j.exger.2006.10.011. View

Hilenski L, Clempus R, Quinn M, Lambeth J, Griendling K . Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003; 24(4):677-83. DOI: 10.1161/01.ATV.0000112024.13727.2c. View

Byrne J, Grieve D, Bendall J, Li J, Gove C, Lambeth J . Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ Res. 2003; 93(9):802-5. DOI: 10.1161/01.RES.0000099504.30207.F5. View

Bendall J, Cave A, Heymes C, Gall N, Shah A . Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation. 2002; 105(3):293-6. DOI: 10.1161/hc0302.103712. View

Bedard K, Krause K . The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007; 87(1):245-313. DOI: 10.1152/physrev.00044.2005. View

Zorov D, Filburn C, Klotz L, Zweier J, Sollott S . Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 2000; 192(7):1001-14. PMC: 2193314. DOI: 10.1084/jem.192.7.1001. View

Sorescu D, Griendling K . Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail. 2002; 8(3):132-40. DOI: 10.1111/j.1527-5299.2002.00717.x. View

Murdoch C, Zhang M, Cave A, Shah A . NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure. Cardiovasc Res. 2006; 71(2):208-15. DOI: 10.1016/j.cardiores.2006.03.016. View

10.

Balaban R, Nemoto S, Finkel T . Mitochondria, oxidants, and aging. Cell. 2005; 120(4):483-95. DOI: 10.1016/j.cell.2005.02.001. View

11.

Serrander L, Cartier L, Bedard K, Banfi B, Lardy B, Plastre O . NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J. 2007; 406(1):105-14. PMC: 1948990. DOI: 10.1042/BJ20061903. View

12.

Martyn K, Frederick L, von Loehneysen K, Dinauer M, Knaus U . Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal. 2005; 18(1):69-82. DOI: 10.1016/j.cellsig.2005.03.023. View

13.

Ide T, Tsutsui H, Hayashidani S, Kang D, Suematsu N, Nakamura K . Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. Circ Res. 2001; 88(5):529-35. DOI: 10.1161/01.res.88.5.529. View

14.

Sumimoto H . Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS J. 2008; 275(13):3249-77. DOI: 10.1111/j.1742-4658.2008.06488.x. View

15.

Gorin Y, Block K, Hernandez J, Bhandari B, Wagner B, Barnes J . Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem. 2005; 280(47):39616-26. DOI: 10.1074/jbc.M502412200. View

16.

Cucoranu I, Clempus R, Dikalova A, Phelan P, Ariyan S, Dikalov S . NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005; 97(9):900-7. DOI: 10.1161/01.RES.0000187457.24338.3D. View

17.

Maytin M, Siwik D, Ito M, Xiao L, Sawyer D, Liao R . Pressure overload-induced myocardial hypertrophy in mice does not require gp91phox. Circulation. 2004; 109(9):1168-71. DOI: 10.1161/01.CIR.0000117229.60628.2F. View

18.

Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P . Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res. 2007; 101(3):258-67. DOI: 10.1161/CIRCRESAHA.107.148015. View

19.

Ji L, Dillon D, Wu E . Myocardial aging: antioxidant enzyme systems and related biochemical properties. Am J Physiol. 1991; 261(2 Pt 2):R386-92. DOI: 10.1152/ajpregu.1991.261.2.R386. View

20.

Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N . Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res. 1999; 85(4):357-63. DOI: 10.1161/01.res.85.4.357. View