PKC-dependent extracellular signal-regulated kinase 1/2 pathway is involved in the inhibition of Ib on AngiotensinII-induced proliferation of vascular smooth muscle cells

Angiotensinll (AngII) induces Vascular smooth muscle cell (VSMC) proliferation, which plays an important role in the development and progression of hypertension. Angll-induced cellular events have been implicated, in part, in the activation of protein kinase C (PKC) and extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we investigated the effect of lb, a novel nonpeptide Angll receptor type I (AT,) antagonist, on the activation of PKC and ERK1/2 in VSMC proliferation induced by Angll. MTT, and [H-3]thymidine incorporation assay showed that Angll-induced VSMC proliferation was inhibited significantly by lb. The specific binding of [1251]Angll to AT, receptors was blocked by lb in a concentration-dependent manner with IC50 value of 0.96 nM. PKC activity assay and Western blot analysis demonstrated that lb significantly inhibited the activation of PKC and phosphorylation of ERK1/2 induced by Angll, respectively. Furthermore, Angll-induced ERK1/2 activation was obviously blocked by GF109203X, a PKC inhibitor. These findings Suggest that the suppression of lb on Angll-induced VSMC proliferation may be attributed to its inhibitory effect on PKC-dependent ERK1/2 pathway. (C) 2008 Elsevier Inc. All rights reserved.