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Activation of Vascular Protein Kinase C-ß Inhibits Akt-Dependent Endothelial Nitric Oxide Synthase Function in Obesity-Associated Insulin Resistance

¹ Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
² Department of Internal Medicine, Aichi-Gakuin University, School of Dentistry, Chikusa-ku, Nagoya, Japan

Address correspondence and reprint requests to George L. King, MD, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Room 4504, Boston, MA 02215. E-mail: george.king{at}joslin.harvard.edu

Abbreviations: BAEC, bovine aortic endothelial cell; DAG, diacylglycerol; DMEM, Dulbecco’s modified Eagle’s medium; eNOS, endothelial nitric oxide synthase; FFA, free fatty acid; GFP, green fluorescent protein; PI, phosphatidylinositol; PKC, protein kinase C; VEGF, vascular endothelial growth factor

Activation of protein kinase C (PKC) in vascular tissue is associated with endothelial dysfunction and insulin resistance. However, the effect of vascular PKC activation on insulin-stimulated endothelial nitric oxide (NO) synthase (eNOS) regulation has not been characterized in obesity-associated insulin resistance. Diacylglycerol (DAG) concentration and PKC activity were increased in the aorta of Zucker fatty compared with Zucker lean rats. Insulin-stimulated increases in Akt phosphorylation and cGMP concentration (a measure of NO bioavailability) after euglycemic-hyperinsulinemic clamp were blunted in the aorta of fatty compared with lean rats but were partly normalized after 2 weeks of treatment with the PKCß inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCß1 and -ß2, but not PKC, -, or -, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCß1 and -ß2, but not PKC or -, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCß2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCß in endothelial cells and vascular tissue inhibits Akt activation by insulin and VEGF, inhibits Akt-dependent eNOS regulation by insulin, and causes endothelial dysfunction in obesity-associated insulin resistance.

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