Key result
Myocyte-specific overexpression of catalase in senescent mice prevented oxidative modification of SERCA at Cys674, preserved SERCA activity, and prevented diastolic dysfunction.
Oxidative modification of SERCA at Cys674 contributes to age-related diastolic dysfunction, highlighting a potential therapeutic target for preserving cardiac relaxation in the aging heart.
Highlights SERCA Cys674 oxidation as a target in age-related diastolic dysfunction; leaves open clinical translation from murine models.
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.
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Qin et al. (2013) studied Impaired cardiac myocyte relaxation in senescent heart. Myocyte-specific overexpression of catalase vs. Wild-type was evaluated on Oxidative modification of SERCA, SERCA activity, and left ventricular relaxation. Myocyte-specific overexpression of catalase in senescent mice prevented oxidative modification of SERCA at Cys674, preserved SERCA activity, and prevented diastolic dysfunction.
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