Contribution of Extracellular Signal-Regulated Kinase to Angiotensin II–Induced Transforming Growth Factor-β1 Expression in Vascular Smooth Muscle Cells

Abstract

Abstract —We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-β 1 (TGF-β 1 ) mRNA levels in hypertensive rats. However, the molecular mechanism whereby Ang II promotes TGF-β 1 expression in vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the role of extracellular signal–regulated kinase (ERK) in Ang II–mediated TGF-β 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-β 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-β 1 mRNA induced by Ang II. Inhibition of Ang II–induced AP-1 activation with c- fos antisense oligodeoxynucleotide led to a significant reduction of TGF-β 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 show that ERK, through AP-1 activation, is involved in Ang II–induced TGF-β 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-β 1 mRNA leads to the increase in its active protein.