title: Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Critical Illness Research, Lawson Health Research Institute, University of Western Ontario, VRL 6th Floor, A6-140, 800 Commissioners Road, London, ON, Canada N6A4G5.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Li
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
authors.forename: Malcolm
authors.initials: M
authors.lastname: Arnold
authors.forename: Tianqing
authors.initials: T
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology; D004789:Enzyme Activation; D006943:Hyperglycemia / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
chemical_list: D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; C033668:calpastatin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002154:Calpain; D053148:Caspase 3; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium