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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp189
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Calpain activation contributes to hyperglycemia-induced apoptosis in cardiomyocytes

Ying Li1,2, Yanwen Li5, Qingping Feng1,2,4, J. Malcolm O. Arnold1,2,4 and Tianqing Peng1,2,3,{dagger}

1 Critical Illness Research, Lawson Health Research Institute
2 Department of Medicine, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK
3 Department of Pathology, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK
4 Department of Physiology and Pharmacology, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK
5 Department of Microbiology, University of Western Ontario, London, Ontario N6A 4G5, Canada

{dagger} Correspondence to: Dr. Tianqing Peng, Critical Illness Research, Lawson Health Research Institute, VRL 6th Floor, A6-140, 800 Commissioners Road, London, Ontario, Canada N6A 4G5, Tel. (519) 685-8300 Ext. 55441. Fax (519) 685-8341. E-mail: tpeng2{at}uwo.ca

Aims: Cardiomyocyte apoptosis contributes to cardiac complications of diabetes. The aim of the present study was to investigate the role of calpain in cardiomyocyte apoptosis induced by hyperglycemia.

Methods and Results: In cultured adult rat ventricular cardiomyocytes, high glucose (33 mM) increased calpain activity and induced apoptosis, concomitant with the impairment of Na+/K+ ATPase activity. These effects of high glucose on cardiomyocytes were abolished by various pharmacological calpain inhibitors, knockdown of calpain-1 but not calpain-2 using siRNA, or over-expression of calpastatin, a specific endogenous calpain inhibitor. The effect of calpain inhibition on cardiomyocyte apoptosis was abrogated by ouabain, a selective inhibitor of Na+/K+ ATPase. Furthermore, blocking gp91phox-NADPH oxidase activation, L-type calcium channels or ryanodine receptors prevented calpain activation and apoptosis in high glucose-stimulated cardiomyocytes. In a mouse model of streptozotocin-induced diabetes, administration of different calpain inhibitors blocked calpain activation, increased the Na+/K+ ATPase activity and decreased apoptosis in the heart.

Conclusions: Calpain-1 activation induces apoptosis through down-regulation of the Na+/K+ ATPase activity in high glucose-stimulated cardiomyocytes and in vivo hyperglycemic hearts. High glucose-induced calpain-1 activation is mediated through the NADPH oxidase dependent pathway and associated with activation of L-type calcium channels and ryanodine receptors. Our data suggest that calpain activation may be important in the development of diabetic cardiomyopathy and thus, may represent a potential therapeutic target for diabetic heart diseases.

Time for primary review: 23 Days


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