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(Hypertension. 1999;34:126-131.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Contribution of Extracellular Signal-Regulated Kinase to Angiotensin II–Induced Transforming Growth Factor-ß1 Expression in Vascular Smooth Muscle Cells

Akinori Hamaguchi; Shokei Kim; Yasukatsu Izumi; Yumei Zhan; Shinya Yamanaka; Hiroshi Iwao

From the Department of Pharmacology, Osaka City University Medical School, Osaka 545-8585, Japan.

Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp

Abstract—We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-ß₁ (TGF-ß₁) mRNA levels in hypertensive rats. However, the molecular mechanism whereby Ang II promotes TGF-ß₁ 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-ß₁ 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-ß₁ 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-ß₁ 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-ß₁ 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-ß₁ 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-ß₁ mRNA leads to the increase in its active protein.

Key Words: muscle, smooth, vascular • angiotensin II • transforming growth factor beta • protein kinases • oligonucleotides, antisense

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