Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells

被引:263
作者
Montagnani, M
Golovchenko, I
Kim, I
Koh, GY
Goalstone, ML
Mundhekar, AN
Johansen, M
Kucik, DF
Quon, MJ
Draznin, B
机构
[1] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA
[2] Pohang Univ Sci & Technol, Natl Creat Res Ctr Endothelial Cells, Pohang 790784, South Korea
[3] Univ Alabama Birmingham, Sch Med, Vet Affairs Med Ctr, Res Serv, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Sch Med, Dept Pathol, Birmingham, AL 35294 USA
[5] Univ Calif San Francisco, Program Host Pathogen Interact, San Francisco, CA 94143 USA
[6] Univ Colorado, Sch Med, Vet Affairs Med Ctr, Res Serv, Denver, CO 80220 USA
[7] Univ Colorado, Sch Med, Dept Med, Denver, CO 80220 USA
关键词
D O I
10.1074/jbc.M103728200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The concept of "selective insulin resistance" has emerged as a unifying hypothesis in attempts to reconcile the influence of insulin resistance with that of hyper-insulinemia in the pathogenesis of macrovascular complications of diabetes. To explore this hypothesis in endothelial cells, we designed a set of experiments to mimic the "typical metabolic insulin resistance" by blocking the phosphatidylinositol 3-kinase pathway and exposing the cells to increasing concentrations of insulin ("compensatory hyperinsulinemia"). Inhibition of phosphatidylinositol 3-kinase with wortmannin blocked the ability of insulin to stimulate increased expression of endothelial nitric-oxide synthase, did not affect insulin-induced activation of MAP kinase, and increased the effects of insulin on prenylation of Ras and Rho proteins. At the same time, this experimental paradigm resulted in increased expression of vascular cellular adhesion molecules-1 and E-selectin, as well as increased rolling interactions of monocytes with endothelial cells. We conclude that inhibition of the metabolic branch of insulin signaling leads to an enhanced mitogenic action of insulin in endothelial cells.
引用
收藏
页码:1794 / 1799
页数:6
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