Abstract 1419: A Novel Role For Protein Kinase C-β In Mediating αvβ3-intracellular Signaling In Vascular Smooth Muscle Cells In The Context Of Hyperglycemia
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. Clinical studies have suggested that inhibition of β3 integrin may distinctly protect diabetics from post-PCI restenosis, a clinical marker for neointimal hyperplasia. Therefore, we sought to determine whether integrin αvβ3 plays a unique role in regulating SMC function in the context of hyperglycemia. Exposure of murine aortic SMCs to elevated glucose (25 mM versus 5 mM) resulted in the association of αvβ3 with protein kinase Cβ (PKCβ; 2.5 ± 0.3 fold increase; P<0.01, Mann Whitney U test), a putative mediator of hyperglycemia-induced signaling. Hyperglycemia also increased the activity of the mitogen activated protein kinase Erk and Akt by 2.26 ± 0.23 and 1.74 ± 0.36 fold, respectively, and activation of Erk was partially dependent on αvβ3 and PKCβ. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required αvβ3, PKCβ, and Erk activity. Additionally, hyperglycemia elevated levels of the integrin ligand thrombospondin (TSP) by 4.26 ± 0.12 fold, in a manner partially dependent on αvβ3 and PKCβ, but not Erk activity. Moreover, TSP-treatment of SMCs cultured in normoglycemic conditions recapitulated the effects of hyperglycemia on Erk activity and migration. These findings were confirmed in aortas from streptozocin-induced diabetic mice, in which the association of αvβ3 with PKCβ correlated with a 4.12 ± 0.43 fold elevation in TSP and a 1.97 ± 0.23 fold increase in Erk activity in wild-type but not integrin β3-deficient vessels. Our results suggest that hyperglycemia promotes the association of PKCβ with αvβ3, which in turn reinforces Erk activation and promotes TSP generation in a positive feedback loop to stimulate SMC proliferation and migration and downstream events involved in diabetic vascular responses.