Induction of Vascular Insulin Resistance and Endothelin-1 Expression and Acceleration of Atherosclerosis by the Overexpression of Protein Kinase C-β Isoform in the Endothelium

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Abstract
Rationale:: Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions. Objective:: To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. Methods and Results:: Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE −/− mice [Tg (Prkcb) apoE −/− ]. On a Western diet, Tg(Prkcb) apoE −/− and apoE −/− mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb) apoE −/− mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb) apoE −/− mice compared with that from apoE −/− mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb) apoE −/− mice compared with apoE −/− mice. The severity of atherosclerosis in the aorta from Tg(Prkcb) apoE −/− mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix. Conclusions:: Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.

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