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(Hypertension. 2004;44:484.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Increased Insulin Receptor Substrate 1 Serine Phosphorylation and Stress-Activated Protein Kinase/c-Jun N-Terminal Kinase Activation Associated With Vascular Insulin Resistance in Spontaneously Hypertensive Rats

From the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston.

Correspondence to Masao Kaneki, MD, PhD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Room 6604, Charlestown, MA 02129. E-mail mkaneki{at}partners.org

Insulin resistance is associated with cardiovascular disease. Impaired insulin receptor substrate (IRS)–mediated signal transduction is a major contributor to insulin resistance. Recently, IRS-1 phosphorylation at serine 307 by stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) has been highlighted as a molecular event that causes insulin resistance. We investigated IRS-1–mediated insulin signaling, IRS-1 phosphorylation at serine 307, and SAPK/JNK activation status in the aorta of spontaneously hypertensive rats (SHR) by immunoprecipitation and immunoblotting. Insulin-stimulated tyrosine phosphorylation of insulin receptor and IRS-1 in SHR was decreased to 55% (P<0.01) and 40% (P<0.01) of the levels in Wistar-Kyoto rats (WKY), respectively. Insulin-stimulated IRS-1–associated phosphatidylinositol 3-kinase activation in SHR was reduced to 28% of the level in WKY (P<0.0001). Immunoblot analysis revealed that phosphorylated IRS-1 at serine 307 in SHR was increased to 261% (P<0.001) of the level in WKY. Phosphorylated (activated) SAPK/JNK in SHR was increased to 223% of the level in WKY (P<0.01). Serine-phosphorylated IRS-1 that was immunoprecipitated from the aorta of SHR was capable of inhibiting in vitro tyrosine phosphorylation by recombinant insulin receptor compared with WKY-derived IRS-1. These findings demonstrate that insulin resistance in the aorta of SHR was associated with elevated IRS-1 phosphorylation at serine 307 and increased SAPK/JNK activation. The present study suggests that increased SAPK/JNK activation may play an important role in the pathogenesis of vascular insulin resistance via inhibitory serine phosphorylation of IRS-1.

Key Words: insulin resistance • rats, spontaneously hypertensive • aorta • phosphorylation • kinase • signal transduction

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