Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart.
Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart.
复制标题
DOI：
10.1161/jaha.113.000184
复制
发表时间：
2013-08-20
影响因子：
5.4
通讯作者：
Colucci WS
中科院分区：
文献类型：
--
作者：
Qin F;Siwik DA;Lancel S;Zhang J;Kuster GM;Luptak I;Wang L;Tong X;Kang YJ;Cohen RA;Colucci WS
心肌细胞老化的标志是由于肌浆网（SR）钙ATP酶（SERCA）活性降低而导致SR钙摄取和松弛受损。我们检验了H2 O2介导的SERCA氧化导致衰老中肌细胞松弛受损的假设。研究了肌细胞特异性过氧化氢酶过表达的年轻（5月龄）和衰老（21月龄）FVB野生型（WT）或转基因小鼠。在衰老小鼠中，过氧化氢酶的肌细胞特异性过表达（1）防止SERCA的氧化修饰，如Cys 674处的磺化所证明的，（2）保留SERCA活性，（3）纠正分离的心肌细胞中受损的钙处理和舒张，（4）防止受损的左心室舒张和舒张功能障碍。硝酰基通过Cys 674处的S-谷胱甘肽化激活SERCA，但未能激活衰老小鼠新鲜分离的心室肌细胞中的SERCA。最后，在原代培养的成年大鼠心室肌细胞中，腺病毒过表达SERCA，其中Cys 674突变为丝氨酸，在暴露于H2 O2期间部分保留SERCA活性。SERCA在Cys 674处的氧化修饰有助于衰老心脏中SERCA活性降低和肌细胞松弛受损。降低氧化水平和/或保护靶蛋白（如SERCA）的策略可能对保护衰老心脏的舒张功能有价值。
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. 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. 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.