Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2014-10, Vol.64 (4), p.738-744
• Main Authors: Liu, Xiaoyu, Kwak, Dongmin, Lu, Zhongbing, Xu, Xin, Fassett, John, Wang, Huan, Wei, Yidong, Cavener, Douglas R, Hu, Xinli, Hall, Jennifer, Bache, Robert J, Chen, Yingjie
• Format: Article
• Language: English
• Subjects: Animals; Aorta - physiopathology; Apoptosis; Blotting, Western; Calcium-Transporting ATPases - metabolism; Cardiomegaly - physiopathology; Constriction; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2 - metabolism; Female; Fibrosis; Heart Failure - physiopathology; Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; Lung - pathology; Lung - physiopathology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Myocardium - metabolism; Myocardium - pathology; Phosphorylation; Pressure; Sarcoplasmic Reticulum - enzymology; Transcription Factor CHOP - metabolism; Ventricular Dysfunction, Left - physiopathology; Weight-Bearing
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.114.03811

Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R–like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2α, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice. Under unstressed conditions, cardiac PERK knockout 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 knockout mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis, and exacerbated lung remodeling in comparison with wild-type mice. PERK knockout 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 congestive heart failure.