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Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in

Keiko Naruse1, Christian Rask-Madsen, Noriko Takahara

  • 1Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.

Diabetes
|March 1, 2006
PubMed

Insights

Protein kinase C beta (PKCβ) activation in blood vessels impairs insulin signaling and nitric oxide production, contributing to endothelial dysfunction in obesity-associated insulin resistance. Inhibiting PKCβ partially restored these functions.

Area of Science:

  • Biochemistry
  • Physiology
  • Endocrinology

Background:

  • Protein kinase C (PKC) activation in vascular tissue is linked to endothelial dysfunction and insulin resistance.
  • The specific role of vascular PKC activation in regulating insulin-stimulated endothelial nitric oxide synthase (eNOS) in obesity-associated insulin resistance remains unclear.

Purpose of the Study:

  • To investigate the effect of vascular PKC activation on insulin-stimulated eNOS regulation in obesity-associated insulin resistance.
  • To determine the specific PKC isoforms involved and their impact on insulin and VEGF signaling pathways.

Main Methods:

  • Comparison of aortic diacylglycerol (DAG) concentration and PKC activity in Zucker fatty and Zucker lean rats.
  • Euglycemic-hyperinsulinemic clamp studies in rats treated with a PKCβ inhibitor (ruboxistaurin).
  • Endothelial cell culture experiments with overexpression of specific PKC isoforms (PKCβ1, PKCβ2, PKCα, PKCδ, PKCζ).
  • Studies in transgenic mice overexpressing PKCβ2 in vascular cells.

Main Results:

  • Increased DAG and PKC activity in the aorta of fatty rats.
  • Blunted insulin-stimulated Akt phosphorylation and cGMP levels in fatty rats, partially normalized by ruboxistaurin.
  • Overexpression of PKCβ1/β2, but not other isoforms, reduced insulin- and VEGF-stimulated Akt phosphorylation and eNOS expression.
  • Vascular cell-specific PKCβ2 overexpression in mice decreased insulin-stimulated Akt phosphorylation.

Conclusions:

  • PKCβ activation in endothelial cells and vascular tissue inhibits insulin and VEGF-stimulated Akt activation.
  • This inhibition impairs Akt-dependent eNOS regulation by insulin.
  • PKCβ activation contributes to endothelial dysfunction in obesity-associated insulin resistance.

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