Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling

Xiaoyu Liu, Dongmin Kwak, Zhongbing Lu, Xin Xu, John Fassett, Huan Wang, Yidong Wei, Douglas R. Cavener, Xinli Hu, Jennifer Hall, Robert J. Bache, Yingjie Chen

Research output: Contribution to journalArticle

38 Scopus citations

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 2a, 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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)738-744
Number of pages7
JournalHypertension
Volume64
Issue number4
DOIs
StatePublished - Jan 1 2014

Keywords

  • Calcium dynamics
  • Cardiomyocytes
  • Congestive heart failure
  • ER stress
  • Endoplasmic reticulum
  • PERK protein
  • Sarcoplasmic endoplasmic reticulum-calcium ATPase

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