Hyperglycemia enhances angiotensin II-induced janus-activated kinase/STAT signaling in vascular smooth muscle cells

We have shown previously that angiotensin II (Ang II) activates the janus-a ctivated kinase (JAK)/signal transducers and activators of transcription (S TAT) pathway in vascular smooth muscle cells (VSMCs) and that activation of the JAK/STAT pathway is required for Ang II induction of VSMC proliferatio n. In the present study, we examined the effects of hyperglycemia (HG) on A ng IT-induced JAK/STAT signaling events in cultured VSMCs. HG increases Ang II-induced JAK2 tyrosine phosphorylation and promotes a partial tyrosine p hosphorylation of the enzyme under basal conditions. In addition, HG increa ses both basal. and Ang II-induced complex formation of JAK2 with the Ang I I AT, receptor. The extent of STAT1 and STAT3 tyrosine and serine phosphory lation are also increased under HG conditions. Furthermore, the tyrosine ph osphorylation and activities of the SHP-1 and SHP-2 tyrosine phosphatases, enzymes that regulate Ang II-induced JAK2 tyrosine phosphorylation, are alt ered by HG. SHP-1, which is responsible for JAK2 tyrosine dephosphorylation in VSMC, is completely deactivated in HG, resulting in a prolonged duratio n of JAK2 phosphorylation under HG conditions. HG also enhances Ang II indu ction of VSMC proliferation. Taken together, these data suggest that HG aug ments Ang II induction of VSMC proliferation by increasing signal transduct ion through the JAK/STAT pathway.