Contribution of extracellular signal-regulated kinase to angiotensin II-induced transforming growth factor-β1 expression in vascular smooth muscle cells

We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-beta(1) (TGF-beta(1)) mRNA levers in hypertensive rats. However, the molecular mechanism whereby Ang II promotes,TGF-beta(1) expression in vascular smooth muscle cells (VSMCs) is poorly understood. Tn this study, we examined the role of extracellular signal-regulated kinase (ERK) in Ang II-mediated TGF-beta(1) expression in VSMCs and the role of Ang II in aortic ERK activity of stroke-prone spontaneously hypertensive rats. Treatment of quiescent VSMCs with 100 nmol/L Ang II induced rapid phosphorylation and activation of ERK1 and ERK2 with a peak at 5 minutes followed by an increase in activator protein-1 (AP-1) DNA binding activity, as shown by gel mobility shift assay. An increase in TGF-beta(1) mRNA was shown by Northern blot analysis. Treatment of VSMCs with PD98059, a specific inhibitor of the ERK pathway, attenuated both the activation of-AP-1 and the increase in TGF-beta(1) mRNA induced by Ang II. Inhibition of Ang II-induced AP-1 activation with c-fos antisense oligodeoxynucleolide led to a significant reduction of TGF-beta 1 mRNA in VSMCs. Furthermore, in vivo treatment of stroke-prone spontaneously hypertensive rats with losartan, an Ang II type 1 receptor antagonist decreased aortic ERK activity Thus, we shaw that ERK, through AP-1 activation, is involved in Ang II-induced TGF-beta(1) mRNA expression in VSMCs and suggest that ERK may participate in vascular remodeling of hypertension. However, it remains to be determined whether the increase in TGF-beta(1) mRNA leads to the increase in its active protein.