Cardiovascular Research Advance Access originally published online on June 8, 2009
Cardiovascular Research 2009 84(1):100-110; doi:10.1093/cvr/cvp189
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Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes
1 Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, Canada N6A 4G5
2 Department of Medicine, University of Western Ontario, London, ON, Canada N6A 4G5
3 Department of Microbiology, Imperial College London, Flowers Building, Armstrong Road, London SW7 2AZ, UK
4 Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada N6A 4G5
5 Department of Pathology, University of Western Ontario, London, ON, Canada N6A 4G5
* Corresponding author. Tel: +1 519 685 8300; fax: +1 519 685 8341. E-mail address: tpeng2{at}uwo.ca
Aims: Cardiomyocyte apoptosis contributes to cardiac complications of diabetes. The aim of this study was to investigate the role of calpain in cardiomyocyte apoptosis induced by hyperglycaemia.
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.
Conclusion: Calpain-1 activation induces apoptosis through down-regulation of the Na+/K+ ATPase activity in high glucose-stimulated cardiomyocytes and in vivo hyperglycaemic 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.
KEYWORDS Cardiomyocyte; Apoptosis; Calpain; NADPH oxidase; Na+/K+ ATPase; High glucose
Time for primary review: 23 days