Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells.
The concept of "selective insulin resistance" has emerged as a unifying hypothesis in attempts to reconcile the influence of insulin resistance with that of hyperinsulinemia 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.
Montagnani
Monica
M
Cardiology Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Golovchenko
Inga
I
Kim
Injune
I
Koh
Gou Young
GY
Goalstone
Marc L
ML
Mundhekar
Ameya N
AN
Johansen
Mette
M
Kucik
Dennis F
DF
Quon
Michael J
MJ
Draznin
Boris
B
D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000209:etiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D008934:Mitogens; D000081082:Phosphoinositide-3 Kinase Inhibitors; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin