Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1862

Article

Li, Shengcun¹  Zhang, Lulu^1,2  Ni, Rui^1,2,6,8  Cao, Ting^1,2  Zheng, Dong^1,2,6,7  Xiong, Sidong^1,2  Greer, Peter A.^3,4  Fan, Guo-Chang⁵  Peng, Tianqing^1,2,6,7,8 

[1] Soochow Univ, Inst Biol, Suzhou 215123, Jiangsu, Peoples R China

[2] Soochow Univ, Inst Med Sci, Suzhou 215123, Jiangsu, Peoples R China

[3] Queens Univ, Div Canc Biol & Genet, Canc Res Inst, Kingston, ON K7L 3N6, Canada

[4] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada

[5] Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA

[6] Western Univ, Lawson Hlth Res Inst, Crit Illness Res, London, ON N6A 4G5, Canada

[7] Western Univ, Dept Med, London, ON N6A 4G5, Canada

[8] Western Univ, Dept Pathol & Lab Med, London, ON N6A 4G5, Canada

关键词: Calpain;    Cardiomyocytes;    Lipotoxicity;    Endoplasmic reticulum stress;   

DOI  :  10.1016/j.bbadis.2016.08.005

来源: Elsevier

【 摘 要 】

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 4 weeks) were fed a high fat diet (HFD) or normal diet for 20 weeks. 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. (C) 2016 Elsevier B.V. All rights reserved.

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