title: Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure.
abstract: BACKGROUND
  Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood.
  
  
  OBJECTIVE
  We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes.
  
  
  RESULTS
  Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of angiotensin II-treated mice. The causal role of mitochondrial ROS in angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase γ, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure.
  
  
  CONCLUSIONS
  These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.
authors.affiliation: Department of Pathology, University of Washington, 1959 Pacific Ave. NE, Seattle, WA 98195, USA.
authors.forename: Dao-Fu
authors.initials: DF
authors.lastname: Dai
authors.forename: Simon C
authors.initials: SC
authors.lastname: Johnson
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Villarin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chin
authors.forename: Madeline
authors.initials: M
authors.lastname: Nieves-Cintrón
authors.forename: Tony
authors.initials: T
authors.lastname: Chen
authors.forename: David J
authors.initials: DJ
authors.lastname: Marcinek
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000503:physiopathology*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004272:DNA, Mitochondrial / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D018894:Reverse Transcriptase Inhibitors; D000804:Angiotensin II; D015215:Zidovudine; D002374:Catalase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11