Endoplasmic reticulum stress sensor PERK protects against pressure overload induced heart failure and lung remodeling

摘要

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.