Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance.
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.
Naruse
Keiko
K
Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Rask-Madsen
Christian
C
Takahara
Noriko
N
Ha
Sung-woo
SW
Suzuma
Kiyoshi
K
Way
Kerrie J
KJ
Jacobs
Judith R C
JR
Clermont
Allen C
AC
Ueki
Kohjiro
K
Ohshiro
Yuzuru
Y
Zhang
Junqing
J
Goldfine
Allison B
AB
King
George L
GL
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D001808:Blood Vessels / Q000201:enzymology*; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D004075:Diglycerides / Q000097:blood; D004789:Enzyme Activation; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors* / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D064546:Protein Kinase C beta; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D011924:Rats, Zucker; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D004075:Diglycerides; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D006152:Cyclic GMP