The roles of calpain and protein kinase C in type 1 diabetic vascular dysfunction
Endothelial dysfunction is an early change associated with cardiovascular disease in diabetes. The calcium-dependent protease calpain is activated in the endothelium by acute hyperglycemia and type 2 diabetes. The endothelial dysfunction associated with diabetic calpain activity is astonishingly similar to that caused by diabetic PKC activity. Biochemical studies indicate bidirectional crosstalk between calpain and PKC in vitro. Therefore, we hypothesized that type 1 diabetes activates vascular calpain in the signaling cascade of vascular PKC to induce endothelial dysfunction in type 1 diabetes. ^ Measurements of the proteolysis of a fluorogenic calpain substrate indicated increased calpain activity in the mesenteric microvasculature of type 1 diabetic rats. Using intravital microscopy, the calpain signal was localized to the endothelium of mesenteric post-capillary venules in vivo. In vitro studies demonstrated that endothelial calpain is activated acutely by hyperglycemia, which is the hallmark of type 1 diabetes. ^ Radioactive measurements indicated that PKC is activated independently of calpain in the type 1 diabetic vasculature. Conversely, type 1 diabetes activates endothelial calpain downstream of PKC, as demonstrated by intravital microscopy of mesenteric post-capillary venules. Local hyperglycemia of the mesenteric microvasculature also increases endothelial calpain in a PKC-dependent manner, thus identifying hyperglycemia as a key activator of PKC-calpain signaling in type 1 diabetes. In vitro experiments implicated the PKC β isoform in the activation of endothelial calpain, and western blot analysis revealed that type 1 diabetes preferentially activates the vascular ì-calpain isoform.^
Amanda R Smolock,
"The roles of calpain and protein kinase C in type 1 diabetic vascular dysfunction"
(January 1, 2010).
ETD Collection for Thomas Jefferson University.