Abstract |
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 PKCbeta inhibitor ruboxistaurin (LY333531). In endothelial cell culture, overexpression of PKCbeta1 and -beta2, but not PKCalpha, -delta, or -zeta, decreased insulin-stimulated Akt phosphorylation and eNOS expression. Overexpression of PKCbeta1 and -beta2, but not PKCalpha or -delta, also decreased Akt phosphorylation stimulated by vascular endothelial growth factor ( VEGF). In microvessels isolated from transgenic mice overexpressing PKCbeta2 only in vascular cells, Akt phosphorylation stimulated by insulin was decreased compared with wild-type mice. Thus, activation of PKCbeta 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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Authors | Keiko Naruse, Christian Rask-Madsen, Noriko Takahara, Sung-woo Ha, Kiyoshi Suzuma, Kerrie J Way, Judith R C Jacobs, Allen C Clermont, Kohjiro Ueki, Yuzuru Ohshiro, Junqing Zhang, Allison B Goldfine, George L King |
Journal | Diabetes
(Diabetes)
Vol. 55
Issue 3
Pg. 691-8
(Mar 2006)
ISSN: 0012-1797 [Print] United States |
PMID | 16505232
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Diglycerides
- Vascular Endothelial Growth Factor A
- Nitric Oxide Synthase Type III
- Proto-Oncogene Proteins c-akt
- Protein Kinase C
- Protein Kinase C beta
- Cyclic GMP
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Topics |
- Animals
- Atherosclerosis
(etiology)
- Blood Vessels
(enzymology)
- Cattle
- Cells, Cultured
- Cyclic GMP
(biosynthesis)
- Diglycerides
(blood)
- Enzyme Activation
- Insulin Resistance
- Male
- Mice
- Mice, Transgenic
- Nitric Oxide Synthase Type III
(antagonists & inhibitors, physiology)
- Obesity
(complications, metabolism)
- Phosphorylation
- Protein Kinase C
(physiology)
- Protein Kinase C beta
- Proto-Oncogene Proteins c-akt
(physiology)
- Rats
- Rats, Zucker
- Vascular Endothelial Growth Factor A
(pharmacology)
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