The anti-apoptotic protein HAX-1 is a regulator of cardiac function
The anti-apoptotic protein HAX-1 is a regulator of cardiac function
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DOI：
10.1073/pnas.0906998106
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发表时间：
2009-12-08
影响因子：
11.1
通讯作者：
Kranias, Evangelia G.
中科院分区：
文献类型：
--
作者：
Zhao, Wen;Waggoner, Jason R.;Kranias, Evangelia G.
HS-1相关蛋白X-1（HAX-1）是一种广泛表达的蛋白质，可保护心肌细胞免于程序性细胞死亡。在这里，我们确定HAX-1作为心脏收缩力和钙循环的调节剂。HAX-1过表达降低了分离的心肌细胞和体内的肌浆网Ca-ATP酶（SERCA 2）泵活性，导致肌细胞钙动力学和力学下降。相反，下调HAX-1增强钙循环和收缩性。HAX-1的抑制作用在受磷蛋白磷酸化后被消除，受磷蛋白在控制基础收缩性中起重要作用，并构成β-肾上腺素能信号级联的关键下游效应物。从机制上讲，HAX-1促进受磷蛋白单体（钙泵的活性/抑制单位）的形成。事实上，PLN的消融挽救了HAX-1对体内收缩性的抑制。因此，HAX-1代表了心脏钙循环及其对交感神经刺激的反应的调节机制，暗示了其在钙稳态和细胞存活中的重要性。
The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as a regulator of contractility and calcium cycling in the heart. HAX-1 overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium kinetics and mechanics. Conversely, downregulation of HAX-1 enhanced calcium cycling and contractility. The inhibitory effects of HAX-1 were abolished upon phosphorylation of phospholamban, which plays a fundamental role in controlling basal contractility and constitutes a key downstream effector of the beta-adrenergic signaling cascade. Mechanistically, HAX-1 promoted formation of phospholamban monomers, the active/inhibitory units of the calcium pump. Indeed, ablation of PLN rescued HAX-1 inhibition of contractility in vivo. Thus, HAX-1 represents a regulatory mechanism in cardiac calcium cycling and its responses to sympathetic stimulation, implicating its importance in calcium homeostasis and cell survival.