Acute Glucose-induced Downregulation of PKC-βII Accelerates Cultured VSMC Proliferation

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atherosclerosis, cell cycle, diabetes mellitus, protein kinase C inhibitor, thymidine

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Accelerated vascular smooth muscle cell (VSMC) proliferation contributes to the formation of atherosclerotic lesions. To investigate protein kinase C (PKC)-βII functions with regard to glucose-induced VSMC proliferation, human VSMC from aorta (AoSMC), a clonal VSMC line of rat aorta (A10), and A10 cells overexpressing PKC-βI (βI-A10) and PKC-βII (βII-A10) were studied with the use of three techniques to evaluate glucose effects on aspects affecting proliferation. High glucose (25 mM) increased DNA synthesis and accelerated cell proliferation compared with normal glucose (5.5 mM) in AoSMC and A10 cells, but not in βI-A10 and βII-A10 cells. The PKC-βII specific inhibitor CGP-53353 inhibited glucose-induced cell proliferation and DNA synthesis in AoSMC and A10 cells. In flow cytometry analysis, high glucose increased the percentage of A10 cells at 12 h after cell cycle initiation but did not increase the percentage of βI-A10 or βII-A10 cells entering S phase. PKC-βII protein levels decreased before the peak of DNA synthesis, and high glucose further decreased PKC-βII mRNA and protein levels in AoSMC and A10 cells. These results suggest that high glucose downregulates endogenous PKC-βII, which then alters the normal inhibitory role of PKC-βII in cell cycle progression, resulting in the stimulation of VSMC proliferation through acceleration of the cell cycle.

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American Journal of Physiology-Cell Physiology, v. 279, issue 3, p. C587-C595