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.

Abstract

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.

• Authors: Michiko Sugita, Hiroki Sugita, Masao Kaneki
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 44 Issue 4 Pg. 484-9 (Oct 2004) ISSN: 1524-4563 [Electronic] United States
• PMID: 15302844 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Insulin Receptor Substrate Proteins
• Irs1 protein, rat
• Phosphoproteins
• Mitogen-Activated Protein Kinase 8

Topics

• Animals
• Aorta (physiology)
• Insulin Receptor Substrate Proteins
• Insulin Resistance (physiology)
• Male
• Mitogen-Activated Protein Kinase 8 (physiology)
• Phosphoproteins (physiology)
• Phosphorylation
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Signal Transduction