Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2)
Extracellular S100A1 protein inhibits apoptosis in ventricular cardiomyocytes via activation of the extracellular signal-regulated protein kinase 1/2 (ERK1/2)
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DOI：
10.1074/jbc.m308587200
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发表时间：
2003-11-28
影响因子：
4.8
通讯作者：
Remppis, A
中科院分区：
文献类型：
--
作者：
Most, P;Boerries, M;Remppis, A
S100A1是一种属于S100蛋白家族的EF-HAND类钙离子结合蛋白。它在心肌中高水平特异表达，被认为是心脏收缩能力的重要调节因子。由于S100A1蛋白在缺血性心肌损伤过程中被释放到细胞外间隙，我们在体外检测了细胞外S100A1蛋白对心肌细胞的保护作用。在这篇报道中，我们展示了细胞外添加的S100A1蛋白通过钙依赖的笼状蛋白介导的过程被内吞到新生心室肌细胞的内膜室。S100A1摄取对2-脱氧葡萄糖和氧化应激诱导的体外培养新生心肌细胞凋亡的保护作用。S100A1介导的抗细胞凋亡作用涉及细胞外信号调节激酶1/2(ERK1/2)生存通路的特异性激活，包括磷脂酶C、蛋白激酶C、丝裂原激活的蛋白激酶1和ERK1/2的激活。相反，S100A1介导的信号通路中既没有L通道的跨膜钙内流，也没有蛋白激酶A的活性。综上所述，本研究为S100A1蛋白作为一种新的体外心脏保护因子提供了证据。这些发现值得推测，损伤依赖的S100A1蛋白从心肌细胞中释放可能是促进在体心肌存活的内在机制。
S100A1 is a Ca2+-binding protein of the EF-hand type that belongs to the S100 protein family. It is specifically expressed in the myocardium at high levels and is considered to be an important regulator of cardiac contractility. Because the S100A1 protein is released into the extracellular space during ischemic myocardial injury, we examined the cardioprotective potential of the extracellular S100A1 protein on ventricular cardiomyocytes in vitro. In this report we show that extracellularly added S100A1 protein is endocytosed into the endosomal compartment of neonatal ventricular cardiomyocytes via a Ca2+-dependent clathrin-mediated process. S100A1 uptake protects neonatal ventricular cardiomyocytes from 2-deoxyglucose and oxidative stress-induced apoptosis in vitro. S100A1-mediated antiapoptotic effects involve specific activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) prosurvival pathway, including activation of phospholipase C, protein kinase C, mitogen-activated protein kinase kinase 1, and ERK1/2. In contrast, neither transsarcolemmal Ca2+ influx via the L-type channel nor protein kinase A activity seems to take part in the S100A1-mediated signaling pathway. In conclusion, this study provides evidence for the S100A1 protein serving as a novel cardioprotective factor in vitro. These findings warrant speculation that injury-dependent release of the S100A1 protein from cardiomyocytes may serve as an intrinsic mechanism to promote survival of the myocardium in vivo.