title: Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress.
abstract: Diabetes and obesity are prevalent in westernized countries. In both conditions, excessive fatty acid uptake by cardiomyocytes induces cardiac lipotoxicity, an important mechanism contributing to diabetic cardiomyopathy. This study investigated the effect of calpain disruption on cardiac lipotoxicity. Cardiac-specific capns1 knockout mice and their wild-type littermates (male, age of 4weeks) were fed a high fat diet (HFD) or normal diet for 20weeks. HFD increased body weight, altered blood lipid profiles and impaired glucose tolerance comparably in both capns1 knockout mice and their wild-type littermates. Calpain activity, cardiomyocyte cross-sectional areas, collagen deposition and triglyceride were significantly increased in HFD-fed mouse hearts, and these were accompanied by myocardial dysfunction and up-regulation of hypertrophic and fibrotic collagen genes as well as pro-inflammatory cytokines. These effects of HFD were attenuated by disruption of calpain in capns1 knockout mice. Mechanistically, deletion of capns1 in HFD-fed mouse hearts and disruption of calpain with calpain inhibitor-III, silencing of capn1, or deletion of capns1 in palmitate-stimulated cardiomyocytes prevented endoplasmic reticulum stress, apoptosis, cleavage of caspase-12 and junctophilin-2, and pro-inflammatory cytokine expression. Pharmacological inhibition of endoplasmic reticulum stress diminished palmitate-induced apoptosis and pro-inflammatory cytokine expression in cardiomyocytes. In summary, disruption of calpain prevents lipotoxicity-induced apoptosis in cardiomyocytes and cardiac injury in mice fed a HFD. The role of calpain is mediated, at least partially, through endoplasmic reticulum stress. Thus, calpain/endoplasmic reticulum stress may represent a new mechanism and potential therapeutic targets for cardiac lipotoxicity.
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors: Shengcun
authors: S
authors: Li
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors: Lulu
authors: L
authors: Zhang
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A 4G5, Canada.
authors: Rui
authors: R
authors: Ni
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors: Ting
authors: T
authors: Cao
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Medicine, Western University, London, Ontario N6A 4G5, Canada.
authors: Dong
authors: D
authors: Zheng
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors: Sidong
authors: S
authors: Xiong
authors: Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario K7L 3N6, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors: Peter A
authors: PA
authors: Greer
authors: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors: Guo-Chang
authors: GC
authors: Fan
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China; Critical Illness Research, Lawson Health Research Institute, Western University, London, Ontario N6A 4G5, Canada; Department of Medicine, Western University, London, Ontario N6A 4G5, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A 4G5, Canada. Electronic address: tpeng2@uwo.ca.
authors: Tianqing
authors: T
authors: Peng
keywords: Calpain; Cardiomyocytes; Endoplasmic reticulum stress; Lipotoxicity