Abstract

Cardiovascular disease is responsible for most of the complications associated with diabetes. Atheroma formation involves the growth and migration of vascular smooth muscle cells (SMCs) in neointimal lesions. Hyperglycemia potentiates chemotaxis of SMCs via PI3K and Erk/MAPK signaling pathways, perhaps through activation of protein kinase Cβ (PKCβ). The aim of this study was to determine if integrin αVβ3 modulated PKCβ activation and effects on PI3K and Erk/MAPK signaling pathways under conditions of hyperglycemia. Under elevated glucose conditions (25mmol/L versus 5 mmol/L), activity of the Erk/MAPK and PI3K pathways were significantly increased in cultured mouse aortic SMCs. The association of PKCβ in a complex with the αVβ3 integrin was observed by immunoprecipitation of lysates from the SMCs. A significant 2.4 fold increase in the association of PKCβ with αVβ3 was observed under conditions of high glucose, and scanning electron microscopy demonstrated a correlation with filapodia formation. In a streptozocin-induced diabetes model in mice, elevated Erk/MAPK and PI3K activity was observed in aortas from mice with blood sugars > 450 mg/dl and was associated with recruitment of PKCβby αVβ3 (Mann Whitney U test, P<0.01). In conclusion, our study suggests that PKCβ is central to αVβ3-mediated intracellular signaling inducing Erk1/2 activation by a novel pathway, which regulate events downstream of adhesion and cell migration involved in diabetic vascular responses. Support: NIH R01HL074219

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