Hyperglycemia Enhances Angiotensin II-induced Janus-activated Kinase/STAT Signaling in Vascular Smooth Muscle Cells

Abstract

We have shown previously that angiotensin II (Ang II) activates the janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in vascular smooth muscle cells (VSMCs) and that activation of the JAK/STAT pathway is required for Ang II induction of VSMC proliferation. In the present study, we examined the effects of hyperglycemia (HG) on Ang II-induced JAK/STAT signaling events in cultured VSMCs. HG increases Ang II-induced JAK2 tyrosine phosphorylation and promotes a partial tyrosine phosphorylation of the enzyme under basal conditions. In addition, HG increases both basal and Ang II-induced complex formation of JAK2 with the Ang II AT 1 receptor. The extent of STAT1 and STAT3 tyrosine and serine phosphorylation are also increased under HG conditions. Furthermore, the tyrosine phosphorylation and activities of the SHP-1 and SHP-2 tyrosine phosphatases, enzymes that regulate Ang II-induced JAK2 tyrosine phosphorylation, are altered by HG. SHP-1, which is responsible for JAK2 tyrosine dephosphorylation in VSMC, is completely deactivated in HG, resulting in a prolonged duration of JAK2 phosphorylation under HG conditions. HG also enhances Ang II induction of VSMC proliferation. Taken together, these data suggest that HG augments Ang II induction of VSMC proliferation by increasing signal transduction through the JAK/STAT pathway.A major pathologic complication of diabetes is atherosclerosis (1). One of the basic underlying causes of diabetic atherosclerosis appears to be hyperglycemia-induced vascular smooth muscle cell (VSMC) 1 proliferation. VSMCs cultured under hyperglycemic (HG) conditions, for example, proliferate at a significantly faster rate than those cultured under normal glucose (NG) conditions (2). HG increases the de novo synthesis of the protein kinase C-activator, diacylglycerol. Thus, one hypothesized mechanism by which HG induces VSMC proliferation is through the chronic activation of one or more isoforms of protein kinase C (3). Other mechanisms by which HG has been suggested to stimulate VSMC proliferation are through nonenzymatic modification of macromolecules to form advanced glycation end products, changes in sorbitol and myoinositol metabolism, increased oxidant formation, and increased production of extracellular matrix molecules (1, 4).VSMC proliferation is also stimulated by a number of growth factors and hormones including angiotensin II (Ang II) (5-8). Furthermore, Ang II stimulation of VSMC proliferation is very likely enhanced by HG because Ang II activation of mitogenactivated protein kinases (MAPKs) is increased in VSMCs cultured under HG conditions (9), and we have shown previously that activation of the MAPK pathway is essential to Ang II induction of VSMC proliferation (7,8). In addition to the MAPK pathway, a second pathway involved in Ang II induction of VSMC proliferation is the janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway (8). The JAK/STAT pathway involves the tyrosine phosphorylation and cons...

S100B-RAGE-Mediated Augmentation of Angiotensin II-Induced Activation of JAK2 in Vascular Smooth Muscle Cells Is Dependent on PLD2

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Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

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