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Chronic depletion of glutathione exacerbates ventricular remodeling and dysfunction in the pressure-overloaded heart.
MedLine Citation:
PMID:  23129588     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodeling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate-cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and -588C/T polymorphism of GCLM gene, which reduces plasma levels of GSH.Methods and ResultsPressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM(-/-) mice were 31% of those in GCLM(+/+) mice. TAC resulted in greater heart and lung weight-to-body weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis and worse survival in GCLM(-/-) than GCLM(+/+) mice. Supplementation of GSH diethyl ester reversed the left ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM(-/-) mice. The prevalence of -588T polymorphism of the GCLM gene was significantly higher in DCM patients (n=205) than in age- and sex-matched control subjects (n=253) (36% vs. 19%, respectively, P < 0.001). The -588T polymorphism increased the risk of DCM that was independent of age, diabetes and systolic blood pressure (OR 3.13, 95% CI 2.28 to 4.44; P < 0.0001). CONCLUSIONS: Chronic depletion of GSH exacerbates remodeling and dysfunction in the pressure overloaded heart. The clinical relevance of this mouse model is supported by a significant association between -588T polymorphism of GCLM gene and patients with DCM.
Authors:
Yosuke Watanabe; Kazuhiro Watanabe; Tsuyoshi Kobayashi; Yukio Saito; Daisuke Fujioka; Takamitsu Nakamura; Jun-Ei Obata; Kenichi Kawabata; Hideto Mishina; Kiyotaka Kugiyama
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-5
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, Chuo, Yamanashi, Japan.
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