Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: roles of Protein Tyrosine Phosphatase-1B.
Insulin resistance is an underlying mechanism of type 2 diabetes and its vascular complications. Recent evidence suggests that crosstalk between angiotensin II (Ang II) and the insulin signaling in vascular smooth muscle cell (VSMC) may contribute to cellular insulin resistance. We hypothesized that Ang II inhibits the anti-mitogenic pathways while enhancing the mitogenic pathways stimulated by insulin via activation of Protein Tyrosine Phosphatase-1B (PTP-1B) in VSMC. We found that Ang II significantly inhibited insulin-induced phosphorylation of tyrosine 608 of IRS-1 and serine 473 of Akt, a downstream member of anti-mitogenic pathway of insulin. In contrast, Ang II increased the serine phosphorylation of IRS-1 which was not affected by the presence of insulin. Activation of p42/p44 MAPK (a mitogenic pathway) induced by insulin was further enhanced by Ang II. Transfection of VSMC with PTP-1B antisense oligonucleotide markedly reduced the effects of Ang II on insulin signaling. Furthermore, an increase in VSMC growth was attenuated by PTP-1B antisense only in the presence of both Ang II and insulin. Finally, we also showed that Ang II-induced activation of PTP-1B in VSMC was PKA/JAK2 dependent. We conclude that Ang II modulates both anti-mitogenic and mitogenic pathways of insulin via the activation of PTP-1B.
Ketsawatsomkron
Pimonrat
P
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA. pim-kets@uiowa.edu
Stepp
David W
DW
Fulton
David J
DJ
Marrero
Mario B
MB
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D007328:Insulin; D000804:Angiotensin II; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1