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Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis.
Diabetologia. 2019 05; 62(5):860-872.D

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.

Authors+Show Affiliations

Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China. Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China. Institute for Cardiovascular Science, Soochow University, Suzhou, China. Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4G5, Canada. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4G5, Canada. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4G5, Canada. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4G5, Canada. Department of Medicine, Western University, London, ON, Canada. Department of Physiology and Pharmacology, Western University, London, ON, Canada.Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Queen's University, Kingston, ON, Canada. Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou, China. Institute for Cardiovascular Science, Soochow University, Suzhou, China.Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China. tpeng2@uwo.ca. Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, N6A 4G5, Canada. tpeng2@uwo.ca. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada. tpeng2@uwo.ca. Department of Medicine, Western University, London, ON, Canada. tpeng2@uwo.ca.

Pub Type(s)

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

Language

eng

PubMed ID

30778623

Citation

Teng, Xiaomei, et al. "Selective Deletion of Endothelial Cell Calpain in Mice Reduces Diabetic Cardiomyopathy By Improving Angiogenesis." Diabetologia, vol. 62, no. 5, 2019, pp. 860-872.
Teng X, Ji C, Zhong H, et al. Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis. Diabetologia. 2019;62(5):860-872.
Teng, X., Ji, C., Zhong, H., Zheng, D., Ni, R., Hill, D. J., Xiong, S., Fan, G. C., Greer, P. A., Shen, Z., & Peng, T. (2019). Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis. Diabetologia, 62(5), 860-872. https://doi.org/10.1007/s00125-019-4828-y
Teng X, et al. Selective Deletion of Endothelial Cell Calpain in Mice Reduces Diabetic Cardiomyopathy By Improving Angiogenesis. Diabetologia. 2019;62(5):860-872. PubMed PMID: 30778623.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis. AU - Teng,Xiaomei, AU - Ji,Chen, AU - Zhong,Huiting, AU - Zheng,Dong, AU - Ni,Rui, AU - Hill,David J, AU - Xiong,Sidong, AU - Fan,Guo-Chang, AU - Greer,Peter A, AU - Shen,Zhenya, AU - Peng,Tianqing, Y1 - 2019/02/18/ PY - 2018/11/18/received PY - 2019/01/14/accepted PY - 2019/2/20/pubmed PY - 2020/2/11/medline PY - 2019/2/20/entrez KW - Calpain KW - Diabetic cardiomyopathy KW - Endothelial cells KW - Neovascularisation KW - β-Catenin SP - 860 EP - 872 JF - Diabetologia JO - Diabetologia VL - 62 IS - 5 N2 - 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. SN - 1432-0428 UR - https://www.unboundmedicine.com/medline/citation/30778623/Selective_deletion_of_endothelial_cell_calpain_in_mice_reduces_diabetic_cardiomyopathy_by_improving_angiogenesis_ L2 - https://doi.org/10.1007/s00125-019-4828-y DB - PRIME DP - Unbound Medicine ER -