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.

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.