title: Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells.
abstract: Diminished insulin action in the vasculature may contribute to the development of cardiovascular diseases in diabetes. We have studied insulin's effects on the phosphatidylinositol (PI) 3-kinase pathway in arterial smooth muscle cells (SMCs) and its inhibition by endothelin (ET)-1, a potent vasoactive hormone reported to be elevated in insulin resistance and other vascular diseases. ET-1 increased the level of serine phosphorylation of insulin receptor beta subunit but increased both tyrosine and serine phosphorylation of insulin receptor substrate (IRS)-2. Pretreatment of cells with ET-1 (10 nmol/l) inhibited insulin-stimulated PI 3-kinase activity associated with IRS-2 by 50-60% and inhibited the association of p85 subunit of PI 3-kinase to IRS-2. The inhibition of insulin-stimulated PI 3-kinase activity by ET-1 was prevented by BQ-123, a selective ET(A) receptor antagonist, but was not affected by pertussis toxin. Treatment of cells with phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), reduced both insulin-stimulated PI 3-kinase activity by 57% and the association of IRS-2 to the p85 subunit of PI 3-kinase by 40%, whereas GF109203X, a specific inhibitor of PKC, partially prevented the inhibitory effect of ET-1 on insulin-induced PI 3-kinase activity. These results suggested that ET-1 could interfere with insulin signaling in SMCs by both PKC-dependent and -independent pathways.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Jiang
authors.forename: Q L
authors.initials: QL
authors.lastname: Zhou
authors.forename: A
authors.initials: A
authors.lastname: Chatterjee
authors.forename: E P
authors.initials: EP
authors.lastname: Feener
authors.forename: M G
authors.initials: MG
authors.lastname: Myers
authors.forename: M F
authors.initials: MF
authors.lastname: White
authors.forename: G L
authors.initials: GL
authors.lastname: King
mesh_terms: D000818:Animals; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010456:Peptides, Cyclic; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D010768:Phosphoserine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D010566:Virulence Factors, Bordetella; C526297:IRS2 protein, human; C526299:Irs2 protein, rat; C072247:cyclo(Trp-Asp-Pro-Val-Leu)