Activation of vascular protein kinase C-β inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance

K Naruse, C Rask-Madsen, N Takahara, S Ha… - Diabetes, 2006 - Am Diabetes Assoc
K Naruse, C Rask-Madsen, N Takahara, S Ha, K Suzuma, KJ Way, JRC Jacobs…
Diabetes, 2006Am Diabetes Assoc
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 …
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 PKCβ inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCβ1 and -β2, but not PKCα, -δ, or -ζ, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCβ1 and -β2, but not PKCα or -δ, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor (VEGF). In microvessels isolated from transgenic mice overexpressing PKCβ2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCβ 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.
Am Diabetes Assoc