Induction of Vascular Insulin Resistance, Endothelin-1 Expression, and Acceleration of Atherosclerosis by the Overexpression of Protein Kinase C β Isoform in the Endothelium
Rationale: Loss of insulin action on the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes can activate protein kinase C (PKC) β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase (PI3K)/Akt pathway to inhibit the activation of endothelial nitric oxide synthase (eNOS) and metabolic actions.
Objective: To demonstrate that overexpressing PKCβ2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.
Methods and Results: PKCβ2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell-cadherin (VE-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 were impaired by ~40% with respect to Akt/eNOS activation and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)ApoE-/- mice compared to ApoE-/- mice. Basal and angiotensin stimulated big endothelin-1 (ET-1) levels were elevated in Tg(Prkcb)ApoE-/- mice compared to 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 PKCβ2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis due to loss of insulin-stimulated Akt/eNOS activation and angiotensin induced increases in ET-1 expression.
- Received January 28, 2013.
- Revision received June 10, 2013.
- Accepted June 11, 2013.