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01-05-2019 | Diabetic Cardiomyopathy | Article

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis

Authors: Xiaomei Teng, Chen Ji, Huiting Zhong, Dong Zheng, Rui Ni, David J. Hill, Sidong Xiong, Guo-Chang Fan, Peter A. Greer, Zhenya Shen, Tianqing Peng

Published in: Diabetologia | Issue 5/2019

Abstract

Aims/hypothesis

The role of non-cardiomyocytes in diabetic cardiomyopathy has not been fully addressed. This study investigated whether endothelial cell calpain plays a role in myocardial endothelial injury and microvascular rarefaction in diabetes, thereby contributing to diabetic cardiomyopathy.

Methods

Endothelial cell-specific Capns1-knockout (KO) mice were generated. Conditions mimicking prediabetes and type 1 and type 2 diabetes were induced in these KO mice and their wild-type littermates. Myocardial function and coronary flow reserve were assessed by echocardiography. Histological analyses were performed to determine capillary density, cardiomyocyte size and fibrosis in the heart. Isolated aortas were assayed for neovascularisation. Cultured cardiac microvascular endothelial cells were stimulated with high palmitate. Angiogenesis and apoptosis were analysed.

Results

Endothelial cell-specific deletion of Capns1 disrupted calpain 1 and calpain 2 in endothelial cells, reduced cardiac fibrosis and hypertrophy, and alleviated myocardial dysfunction in mouse models of diabetes without significantly affecting systemic metabolic variables. These protective effects of calpain disruption in endothelial cells were associated with an increase in myocardial capillary density (wild-type vs Capns1-KO 3646.14 ± 423.51 vs 4708.7 ± 417.93 capillary number/high-power field in prediabetes, 2999.36 ± 854.77 vs 4579.22 ± 672.56 capillary number/high-power field in type 2 diabetes and 2364.87 ± 249.57 vs 3014.63 ± 215.46 capillary number/high-power field in type 1 diabetes) and coronary flow reserve. Ex vivo analysis of neovascularisation revealed more endothelial cell sprouts from aortic rings of prediabetic and diabetic Capns1-KO mice compared with their wild-type littermates. In cultured cardiac microvascular endothelial cells, inhibition of calpain improved angiogenesis and prevented apoptosis under metabolic stress. Mechanistically, deletion of Capns1 elevated the protein levels of β-catenin in endothelial cells of Capns1-KO mice and constitutive activity of calpain 2 suppressed β-catenin protein expression in cultured endothelial cells. Upregulation of β-catenin promoted angiogenesis and inhibited apoptosis whereas knockdown of β-catenin offset the protective effects of calpain inhibition in endothelial cells under metabolic stress.

Conclusions/interpretation

These results delineate a primary role of calpain in inducing cardiac endothelial cell injury and impairing neovascularisation via suppression of β-catenin, thereby promoting diabetic cardiomyopathy, and indicate that calpain is a promising therapeutic target to prevent diabetic cardiac complications.

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Title: Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis
Authors: Xiaomei Teng
Chen Ji
Huiting Zhong
Dong Zheng
Rui Ni
David J. Hill
Sidong Xiong
Guo-Chang Fan
Peter A. Greer
Zhenya Shen
Tianqing Peng
Publication date: 01-05-2019
Publisher: Springer Berlin Heidelberg
Keywords: Diabetic Cardiomyopathy
Prediabetes
Type 1 Diabetes
Published in: Diabetologia / Issue 5/2019
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4828-y

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