Volume 272, Number 43, Issue of October 24, 1997 pp. 26879-26886
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Cyclic AMP-mediated Inhibition of Angiotensin II-induced Protein Synthesis Is Associated with Suppression of Tyrosine Phosphorylation Signaling in Vascular Smooth Muscle Cells

(Received for publication, March 31, 1997, and in revised form, July 3, 1997)

From the Centre de Recherche, Hôtel-Dieu de Montréal and Department of Pharmacology, University of Montreal, Montreal, Quebec H2W 1T8, Canada

In the present study, we have examined the effect of increased cyclic AMP (cAMP) levels on the stimulatory action of angiotensin II (Ang II) on protein synthesis. Treatment with cAMP-elevating agents potently inhibited Ang II-induced protein synthesis in rat aortic smooth muscle cells and in rat fibroblasts expressing the human AT₁ receptor. The inhibition was dose-dependent and was observed at all concentrations of the peptide. To explore the mechanism of cAMP action, we have analyzed the effects of forskolin and 3-isobutyl-1-methylxanthine on various receptor-mediated responses. Elevation of cAMP did not alter the binding properties of the AT₁ receptor and did not interfere with the activation of phospholipase C or the induction of early growth response genes by Ang II. Likewise, Ang II-dependent activation of the mitogen-activated protein kinases ERK1/ERK2 and p70 S6 kinase was unaffected by cAMP. In contrast, we found that increased concentration of cAMP strongly inhibited the stimulatory effect of Ang II on protein tyrosine phosphorylation. Specifically, cAMP abolished Ang II-induced tyrosine phosphorylation of the focal adhesion-associated protein paxillin and of the tyrosine kinase Tyk2. These results identify a novel mechanism by which the cAMP signaling system may exert growth-inhibitory effects in specific cell types.

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