title: Upregulation of Nox4 by hypertrophic stimuli promotes apoptosis and mitochondrial dysfunction in cardiac myocytes.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Newark, NJ 07103, USA.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Jayashree
authors.initials: J
authors.lastname: Pain
authors.forename: Cexiong
authors.initials: C
authors.lastname: Fu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003545:Cysteine; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009245:NADH Dehydrogenase / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D014475:Uncoupling Agents / Q000494:pharmacology; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D004791:Enzyme Inhibitors; D009861:Onium Compounds; D014475:Uncoupling Agents; D012402:Rotenone; D013481:Superoxides; C007517:diphenyleneiodonium; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C498911:Nox4 protein, rat; D009245:NADH Dehydrogenase; D000154:Aconitate Hydratase; D003545:Cysteine