Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart

Qin, Fuzhong and Siwik, Deborah A. and Lancel, Steve and Zhang, Jingmei and Kuster, Gabriela M. and Luptak, Ivan and Wang, Lei and Tong, Xiaoyong and Kang, Y. James and Cohen, Richard A. and Colucci, Wilson S.. (2013) Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. Journal of the American Heart Association, Vol. 2, H. 4 , e000184.

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Official URL: http://edoc.unibas.ch/dok/A6338359

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BACKGROUND: A hallmark of aging of the cardiac myocyte is impaired sarcoplasmic reticulum (SR) calcium uptake and relaxation due to decreased SR calcium ATPase (SERCA) activity. We tested the hypothesis that H2O2-mediated oxidation of SERCA contributes to impaired myocyte relaxation in aging. METHODS AND RESULTS: Young (5-month-old) and senescent (21-month-old) FVB wild-type (WT) or transgenic mice with myocyte-specific overexpression of catalase were studied. In senescent mice, myocyte-specific overexpression of catalase (1) prevented oxidative modification of SERCA as evidenced by sulfonation at Cys674, (2) preserved SERCA activity, (3) corrected impaired calcium handling and relaxation in isolated cardiac myocytes, and (4) prevented impaired left ventricular relaxation and diastolic dysfunction. Nitroxyl, which activates SERCA via S-glutathiolation at Cys674, failed to activate SERCA in freshly isolated ventricular myocytes from senescent mice. Finally, in adult rat ventricular myocytes in primary culture, adenoviral overexpression of SERCA in which Cys674 is mutated to serine partially preserved SERCA activity during exposure to H2O2. CONCLUSION: Oxidative modification of SERCA at Cys674 contributes to decreased SERCA activity and impaired myocyte relaxation in the senescent heart. Strategies to decrease oxidant levels and/or protect target proteins such as SERCA may be of value to preserve diastolic function in the aging heart.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Myocardial Research (Kuster Pfister)
UniBasel Contributors:Kuster Pfister, Gabriela
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:04 Sep 2015 14:32
Deposited On:10 Apr 2015 09:12

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