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Open Access Original investigation

Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes

Bainian Chen123, Qing Zhao35, Rui Ni24, Futian Tang23, Limei Shan23, Inga Cepinskas2, Gediminas Cepinskas2, Wang Wang6, Peter W Schiller7 and Tianqing Peng12348*

Author Affiliations

1 Institute for Cardiovascular Science of Soochow University, Suzhou, Jiangsu Province 215123, China

2 Lawson Health Research Institute, London Health Sciences Centre, London N6A 4G5, Ontario, Canada

3 Department of Medicine, University of Western Ontario, London N6A 4G5, Ontario, Canada

4 Department of Pathology, University of Western Ontario, London N6A 4G5, Ontario, Canada

5 Department of Cardiology, Shanghai 6th People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China

6 Mitochondria and Metabolism Center, Departments of Anesthesiology and Pain Medicine, University of Washington, Seattle, USA

7 Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada

8 Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada

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Cardiovascular Diabetology 2014, 13:88  doi:10.1186/1475-2840-13-88

Published: 3 May 2014

Abstract

Aims

The present study was to investigate the role of calpain in reactive oxygen species (ROS) production in endothelial cells and endothelium-dependent vascular dysfunction under experimental conditions of diabetes.

Methods and results

Exposure to high glucose activated calpain, induced apoptosis and reduced nitric oxide (NO) production without changing eNOS protein expression, its phosphorylation and dimers formation in primary human umbilical vein endothelial cells (HUVECs). These effects of high glucose correlated with intracellular ROS production and mitochondrial superoxide generation. Selectively scavenging mitochondrial superoxide increased NO production in high glucose-stimulated HUVECs. Inhibition of calpain using over-expression of calpastatin or pharmacological calpain inhibitor prevented high glucose-induced ROS production, mitochondrial superoxide generation and apoptosis, which were concurrent with an elevation of NO production in HUVECs. In mouse models of streptozotocin-induced type-1 diabetes and OVE26 type-1 diabetic mice, calpain activation correlated with an increase in ROS production and peroxynitrite formation in aortas. Transgenic over-expression of calpastatin reduced ROS production and peroxynitrite formation in diabetic mice. In parallel, diabetes-induced reduction of endothelium-dependent relaxation in aortic ring was reversed by over-expression of calpastatin in mouse models of diabetes. However, the protective effect of calpastatin on endothelium-dependent relaxation was abrogated by eNOS deletion in diabetic mice.

Conclusions

This study suggests that calpain may play a role in vascular endothelial cell ROS production and endothelium-dependent dysfunction in diabetes. Thus, calpain may be an important therapeutic target to overcome diabetes-induced vascular dysfunction.

Keywords:
Diabetes; Calpain; eNOS; ROS; Endothelial dysfunction