Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.
Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.
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DOI：
10.1161/hypertensionaha.114.03811
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Liu X;Kwak D;Lu Z;Xu X;Fassett J;Wang H;Wei Y;Cavener DR;Hu X;Hall J;Bache RJ;Chen Y
研究报道，充血性心力衰竭（CHF）的发展与内质网（ER）应激增加有关。双链RNA激活蛋白激酶样内质网激酶（PERK）是内质网应激反应的主要换能器，并直接磷酸化eIF2α，导致翻译衰减。然而，PERK对CHF发展的生理作用尚不清楚。为了研究PERK对心室结构和功能的影响，我们培育了可诱导的心脏特异性PERK敲除（KO）小鼠。在非应激条件下，心脏PERK KO对左心室质量、其与体重的比值、心肌细胞大小、纤维化或左心室功能没有影响。然而，与野生型小鼠相比，在慢性主动脉横缩的反应中，PERK KO小鼠表现出射血分数降低、左心室纤维化增加、心肌细胞凋亡增强和肺重构加剧。PERK KO还能显著降低主动脉收缩时心肌浆网Ca++- atp酶的表达。我们的研究结果表明，PERK是保护心脏免受压力过载引起的心力衰竭所必需的。
Studies have reported that development of congestive heart failure (CHF) is associated with increased endoplasmic reticulum (ER) stress. Double stranded RNA activated protein kinase-like endoplasmic reticulum kinase (PERK) is a major transducer of the ER stress response and directly phosphorylates eIF2α, resulting in translational attenuation. However, the physiological effect of PERK on CHF development is unknown. In order to study the effect of PERK on ventricular structure and function, we generated inducible cardiac specific PERK knockout (KO) mice. Under unstressed conditions, cardiac PERK KO had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK KO mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis and exacerbated lung remodeling in comparison to wild type mice. PERK KO also dramatically attenuated cardiac sarcoplasmic reticulum Ca++-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced CHF.