Open AccessHydrogen Peroxide–Mediated SERCA Cysteine 674 Oxidation Contributes to Impaired Cardiac Myocyte Relaxation in Senescent Mouse Heart
Author(s) -
Qin Fuzhong,
Siwik Deborah A.,
Lancel Steve,
Zhang Jingmei,
Kuster Gabriela M.,
Luptak Ivan,
Wang Lei,
Tong Xiaoyong,
Kang Y. James,
Cohen Richard A.,
Colucci Wilson S.
Publication year - 2013
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.113.000184
Subject(s) - serca , myocyte , phospholamban , medicine , endocrinology , cardiac myocyte , endoplasmic reticulum , heart failure , oxidative stress , microbiology and biotechnology , biology , atpase , biochemistry , enzyme
Background A hallmark of aging of the cardiac myocyte is impaired sarcoplasmic reticulum ( SR ) calcium uptake and relaxation due to decreased SR calcium ATP ase ( SERCA ) activity. We tested the hypothesis that H 2 O 2 ‐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 H 2 O 2 . 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.