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- Title
Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells.
- Authors
Jiang, Zhen Y.; Zhou, Qiong-Lin; Chatterjee, Alakanauda; Feener, Edward P.; Myers Jr., Martin G.; White, Morris F.; King, George L.; Jiang, Z Y; Zhou, Q L; Chatterjee, A; Feener, E P; Myers, M G Jr; White, M F; King, G L
- 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.
- Subjects
ENDOTHELINS; INSULIN; SMOOTH muscle; PHOSPHORYLATION; SERINE metabolism; ANIMALS; BACTERIAL toxins; CARCINOGENS; CARRIER proteins; CELLULAR signal transduction; ENZYME inhibitors; PEPTIDES; PHOSPHOPROTEINS; PHOSPHOTRANSFERASES; RATS; RESEARCH funding; TRANSFERASES; SIGNAL peptides; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Diabetes, 1999, Vol 48, Issue 5, p1120
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.48.5.1120