Mutation of the SERCA-Reactive Cysteine-674 to Serine Attenuates Left Ventricular Hypertrophy and Diastolic Dysfunction in Senescent Mice

Background We have shown previously that oxidation of sarcoplasmic reticulum calcium ATPase (SERCA) cysteine-674 was associated with left ventricular (LV) hypertrophy and diastolic dysfunction in senescent mice. In the present study, we tested the hypothesis that mutation of the SERCA-reactive cysteine-674 to serine (C674S), thereby protecting it from oxidation at this site, will attenuate LV hypertrophy and diastolic dysfunction in senescent mice. Methods Young (5-month-old) and senescent (24-month-old) wild-type (WT) or SERCA C674S knock-in (SKI) mice (n=5-8 per group) were studied. We measured LV structure and function by echocardiography, myocyte cross-sectional area by hematoxylin and eosin staining, and myocardial 4-hydroxynonenal (4-HNE) expression by immunohistochemical staining. Results Conventional echocardiography in senescent WT mice demonstrated an increase in LV total wall thickness (TWTh, 1.84±0.05 vs. 1.45±0.03 mm in Young WT) with preserved LV dimension and systolic function. Mitral inflow and tissue Doppler echocardiography in senescent mice showed prolongation of LV isovolumetric relaxation time and deceleration time of early filling in association with decreases in the ratio of peak early-to-late transmitral velocity (E/A ratio, 1.16±0.04 vs. 1.80±0.04 in Young WT) and diastolic myocardial tissue velocity (E m , 18.9±1.5 vs. 26.2±0.5 mm/sec in Young WT), a pattern typical of abnormal relaxation. All of these abnormalities in LV wall thickness and diastolic function were attenuated (p m : 25.8±0.6 m m/sec). Likewise, in senescent mice the increases in heart weight and myocyte cross-sectional area were attenuated in senescent SKI mice (p Conclusion Protection of SERCA from oxidation at C674S attenuates aging-induced LV hypertrophy and diastolic dysfunction, suggesting that strategies to protect oxidant target proteins such as SERCA are implicated in preserving diastolic function in the aging heart.