Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes

Cardiovasc Res. 2009 Oct 1;84(1):100-10. doi: 10.1093/cvr/cvp189. Epub 2009 Jun 8.


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 gp91(phox)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism
  • Calcium Channels / physiology
  • Calcium-Binding Proteins / physiology
  • Calpain / antagonists & inhibitors
  • Calpain / physiology*
  • Caspase 3 / physiology
  • Enzyme Activation
  • Hyperglycemia / pathology*
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology*
  • NADPH Oxidase 2
  • NADPH Oxidases / physiology
  • Sodium-Potassium-Exchanging ATPase / physiology


  • Calcium Channels
  • Calcium-Binding Proteins
  • Membrane Glycoproteins
  • calpastatin
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Calpain
  • Caspase 3
  • Sodium-Potassium-Exchanging ATPase
  • Calcium