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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice.
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Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice.

机译：心肌特异性肌钙蛋白的过度表达抑制了肌浆网（内质网）Ca2 + ATPase（SERCA2a）的活性，并损害了小鼠的心脏功能。

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Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca(2+) was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca(2+) transients and peak tensions were reduced, whereas decay times of Ca(2+) transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.
机译：Sarcolipin（SLN）通过直接结合抑制心脏的sarco（endo）质网Ca（2+）ATPase（SERCA2a），并且如果通过phospholamban（PLN）结合则具有超强抑制作用。为了确定心脏中SLN的过度表达是否会损害心脏功能，生成了具有心脏特异性NF-SLN（在FLN表位的N端标记有SLN）的心脏特异性转基因（TG）小鼠。 NF-SLN表达水平（NF-SLN / PLN表达比）与在HEK-293细胞中与PLN和SERCA2a共表达时诱导深层超抑制的水平相当。在TG的心脏，与非TG同窝对照心脏相比，SERCA2a对Ca（2+）的表观亲和力降低。侵入性血液动力学和超声心动图分析显示TG小鼠的心脏收缩力和心室肥大受损。基础PLN磷酸化减少。在等轴测张力的孤立的乳头肌中，Ca（2+）瞬态和峰值张力的峰值幅度减小，而TG（TG）小鼠中Ca（2+）瞬态的衰减时间和张力的松弛时间增加。异丙肾上腺素可在很大程度上恢复乳头肌的收缩力，并在完整的心脏中将PLN磷酸化刺激至野生型水平。在TG心脏中未观察到SERCA2a，PLN，ryanodine受体和calsequestrin表达的补偿性变化。共免疫沉淀表明，过表达的NF-SLN与SERCA2a和PLN都结合，形成三元复合物。这些数据表明，NF-SLN过表达通过在不存在PLN磷酸化的情况下稳定SERCA2a-PLN相互作用并通过抑制PLN磷酸化来抑制SERCA2a。抑制SERCA2a会损害收缩力和钙循环，但对β-肾上腺素能激动剂的反应性可能会阻止心脏衰竭的发展。

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