Journal article
Mitochondrial oxidative stress mediates Angiotensin II-induced cardiac hypertrophy and Gαq overexpression-induced heart failure
Circulation research, Vol.108(7), pp.837-846
04/01/2011
DOI: 10.1161/CIRCRESAHA.110.232306
PMCID: PMC3785241
PMID: 21311045
Abstract
Rationale:
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.
Methods and 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.
Details
- Title: Subtitle
- Mitochondrial oxidative stress mediates Angiotensin II-induced cardiac hypertrophy and Gαq overexpression-induced heart failure
- Creators
- Dao-Fu Dai - Department of Pathology, University of Washington, SeattleSimon C Johnson - Department of Pathology, University of Washington, SeattleJason J Villarin - Department of Radiology, University of Washington, SeattleMichael T Chin - Department of Cardiovascular Medicine, University of Washington, SeattleMadeline Nieves-Cintrón - Department of Physiology and Biophysics, University of Washington, SeattleTony Chen - Department of Pathology, University of Washington, SeattleDavid J Marcinek - Department of Radiology, University of Washington, SeattleGerald W Dorn - Department of Internal Medicine, Washington University School of Medicine, St. Louis, MOY. James Kang - Departments of Medicine, and Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KYTomas A Prolla - Department of Genetics & Medical Genetics, University of Wisconsin-MadisonLuis F Santana - Department of Physiology and Biophysics, University of Washington, SeattlePeter S Rabinovitch - Department of Pathology, University of Washington, Seattle
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.108(7), pp.837-846
- DOI
- 10.1161/CIRCRESAHA.110.232306
- PMID
- 21311045
- PMCID
- PMC3785241
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- P01 AG001751 || AG / National Institute on Aging : NIA P30 AG013280 || AG / National Institute on Aging : NIA R01 AG028455 || AG / National Institute on Aging : NIA RC1 AG035844 || AG / National Institute on Aging : NIA R01 HL101186 || HL / National Heart, Lung, and Blood Institute : NHLBI
- Language
- English
- Date published
- 04/01/2011
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984046822002771
Metrics
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