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

Cardiovascular Diabetology

Tianqing Peng⁵  Peter W Schiller¹  Wang Wang²  Gediminas Cepinskas⁶  Inga Cepinskas⁶  Limei Shan⁴  Futian Tang⁴  Rui Ni⁷  Qing Zhao³  Bainian Chen⁴ 

[1] Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada;Mitochondria and Metabolism Center, Departments of Anesthesiology and Pain Medicine, University of Washington, Seattle, USA;Department of Cardiology, Shanghai 6th People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233, China;Department of Medicine, University of Western Ontario, London N6A 4G5, Ontario, Canada;Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada;Lawson Health Research Institute, London Health Sciences Centre, London N6A 4G5, Ontario, Canada;Department of Pathology, University of Western Ontario, London N6A 4G5, Ontario, Canada

关键词: Endothelial dysfunction;    ROS;    eNOS;    Calpain;    Diabetes;   

Others  :  793025
DOI  :  10.1186/1475-2840-13-88

 received in 2014-01-20, accepted in 2014-04-25,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Chen et al.; licensee BioMed Central Ltd.

【 图 表 】

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