Ablation of sarcolipin results in atrial remodeling.
Ablation of sarcolipin results in atrial remodeling.
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DOI：
10.1152/ajpcell.00425.2011
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发表时间：
2012-06
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影响因子：
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通讯作者：
Lai-Hua Xie;M. Shanmugam;Ji Yeon Park;Zhenghang Zhao;Hairuo Wen;Bin Tian;M. Periasamy;G. Babu
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作者：
Lai-Hua Xie;M. Shanmugam;Ji Yeon Park;Zhenghang Zhao;Hairuo Wen;Bin Tian;M. Periasamy;G. Babu
肌磷脂（Sarcolipin，SLN）是肌浆网（sarco（endo）plasmic reticulum，SR）Ca（2+）-ATPase（SERCA）的重要调节因子，其表达在病变心房肌中发生改变。为了确定SLN在心房Ca（2+）稳态中的确切作用，我们开发了SLN敲除（sln-/-）小鼠模型，并证明SLN消融增强心房SERCA泵活性。本研究旨在确定增强的SERCA活性对sln-/-小鼠心房重构的长期影响。钙瞬变测量显示心房SR Ca（2+）负荷和抽搐Ca（2+）瞬变增加。膜片钳实验表明，在sln-/-小鼠的心房肌细胞中，钠/钙交换器的正向模式被激活，L型Ca（2+）通道活性增加，90%复极化时的动作电位时程延长。自发性Ca（2+）波、延迟后除极和触发活动在sln-/-小鼠的心房肌细胞中频繁发生。此外，心房中SLN的丢失与间质纤维化增加和编码胶原蛋白和其他细胞外基质蛋白的基因表达改变有关。我们的研究结果还表明，sln-/-小鼠易受房性心律失常老化。总之，这些发现表明SLN消融导致SERCA活性和SR Ca（2+）负荷增加，进而可能导致细胞内Ca（2+）处理异常和心房重构。
Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca(2+) homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long-term effects of enhanced SERCA activity on atrial remodeling in the sln-/- mice. Calcium transient measurements show an increase in atrial SR Ca(2+) load and twitch Ca(2+) transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/calcium exchanger, increased L-type Ca(2+) channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca(2+) waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca(2+) load, which, in turn, could cause abnormal intracellular Ca(2+) handling and atrial remodeling.