Over-expression of calpastatin inhibits calpain activation and attenuates post-infarction myocardial remodeling

Tingqiao Ye; Qiang Wang; Yan Zhang; Xiaofeng Song; Dachun Yang; De Li; Dan Li; Linan Su; Yongjian Yang; Shuangtao Ma

doi:10.1371/journal.pone.0120178

Over-expression of calpastatin inhibits calpain activation and attenuates post-infarction myocardial remodeling

PLoS One. 2015 Mar 18;10(3):e0120178. doi: 10.1371/journal.pone.0120178. eCollection 2015.

Authors

Tingqiao Ye¹, Qiang Wang¹, Yan Zhang¹, Xiaofeng Song¹, Dachun Yang¹, De Li¹, Dan Li¹, Linan Su¹, Yongjian Yang¹, Shuangtao Ma¹

Affiliation

¹ Department of Cardiology, Chengdu Military General Hospital, Chengdu, Sichuan, China.

Abstract

Background: Calpain is activated following myocardial infarction and ablation of calpastatin (CAST), an endogenous inhibitor of calpains, promotes left ventricular remodeling after myocardial infarction (MI). The present study aimed to investigate the effect of transgenic over-expression of CAST on the post-infarction myocardial remodeling process.

Method: We established transgenic mice (TG) ubiquitously over-expressing human CAST protein and produced MI in TG mice and C57BL/6J wild-type (WT) littermates.

Results: The CAST protein expression was profoundly upregulated in the myocardial tissue of TG mice compared with WT littermates (P < 0.01). Overexpression of CAST significantly reduced the infarct size (P < 0.01) and blunted MI-induced interventricular hypertrophy, global myocardial fibrosis and collagen I and collagen III deposition, hypotension and hemodynamic disturbances at 21 days after MI. Moreover, the MI-induced up-regulation and activation of calpains were obviously attenuated in CAST TG mice. MI-induced down-regulation of CAST was partially reversed in TG mice. Additionally, the MI-caused imbalance of matrix metalloproteinases and their inhibitors was improved in TG mice.

Conclusions: Transgenic over-expression of CAST inhibits calpain activation and attenuates post-infarction myocardial remodeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Calpain / genetics*
Calpain / metabolism
Cardiomegaly / enzymology
Cardiomegaly / genetics*
Cardiomegaly / mortality
Cardiomegaly / pathology
Collagen Type I / genetics
Collagen Type I / metabolism
Collagen Type III / genetics
Collagen Type III / metabolism
Cytoskeletal Proteins / genetics*
Cytoskeletal Proteins / metabolism
Disease Models, Animal
Enzyme Activation
Female
Fibrosis
Gene Expression Regulation
Humans
Isoenzymes / genetics
Isoenzymes / metabolism
Male
Matrix Metalloproteinase Inhibitors / metabolism
Matrix Metalloproteinases, Secreted / genetics
Matrix Metalloproteinases, Secreted / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardial Infarction / enzymology
Myocardial Infarction / genetics*
Myocardial Infarction / mortality
Myocardial Infarction / pathology
Survival Analysis
Ventricular Function, Left / genetics*
Ventricular Remodeling / genetics*

Substances

Collagen Type I
Collagen Type III
Cytoskeletal Proteins
Erc2 protein, mouse
Isoenzymes
Matrix Metalloproteinase Inhibitors
Calpain
Matrix Metalloproteinases, Secreted

Grants and funding

This work was supported by a grant from the Natural Science Foundation of China (No. 81070191) and a grant from the Chengdu Military General Hospital (No. 2011YG-A11). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.