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.

Li Q, Park K, Li C, Rask-Madsen C, Mima A, Qi W, Mizutani K, Huang P, King GL
Circ Res. 2013 113 (4): 418-27

PMID: 23759514 · PMCID: PMC3893704 · DOI:10.1161/CIRCRESAHA.113.301074

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.

MeSH Terms (18)

Animals Aorta Apolipoproteins E Atherosclerosis Disease Models, Animal Endothelin-1 Endothelium, Vascular Female Insulin Resistance Isoenzymes Male Mice Mice, Knockout Nitric Oxide Synthase Type III Protein Kinase C beta Proto-Oncogene Proteins c-akt Up-Regulation Vascular Cell Adhesion Molecule-1

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