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.
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.
Sugita
Michiko
M
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Sugita
Hiroki
H
Kaneki
Masao
M
D000818:Animals; D001011:Aorta / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction
D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D048055:Mitogen-Activated Protein Kinase 8