title: Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.
abstract: 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(2+)-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.
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Xiaoyu
authors: X
authors: Liu
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Dongmin
authors: D
authors: Kwak
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Zhongbing
authors: Z
authors: Lu
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Xin
authors: X
authors: Xu
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: John
authors: J
authors: Fassett
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Huan
authors: H
authors: Wang
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Yidong
authors: Y
authors: Wei
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Douglas R
authors: DR
authors: Cavener
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Xinli
authors: X
authors: Hu
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Jennifer
authors: J
authors: Hall
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.).
authors: Robert J
authors: RJ
authors: Bache
authors: From the Department of Chinese Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China (X.L., Y.W.); Cardiovascular Division, Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis (X.L., D.K., Z.L., X.X., J.F., H.W., J.H., R.J.B., Y.C.); College of Life Science, University of Chinese Academy of Science, Beijing, China (Z.L.); Department of Biology and The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park (D.R.C.); and Institute of Molecular Medicine, Peking University, Beijing, China (X.H.). chenx106@umn.edu.
authors: Yingjie
authors: Y
authors: Chen
mesh_terms: D000818:Animals; D001011:Aorta / Q000503:physiopathology; D017209:Apoptosis; D015153:Blotting, Western; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology; D003250:Constriction; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011312:Pressure; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D051742:Transcription Factor CHOP / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D016474:Weight-Bearing; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000252:Calcium-Transporting ATPases; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C497250:Ddit3 protein, mouse; C018551:glucose-regulated proteins
keywords: ER stress; PERK protein; calcium dynamics; cardiomyocytes; congestive heart failure; endoplasmic reticulum; sarcoplasmic endoplasmic reticulum-calcium ATPase