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Circulation Research. 2001;88:637-644

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(Circulation Research. 2001;88:637.)
© 2001 American Heart Association, Inc.

Molecular Medicine

Retinoids Inhibit the Actions of Angiotensin II on Vascular Smooth Muscle Cells

Volker Haxsen, Sylvie Adam-Stitah, Eberhard Ritz, Jürgen Wagner

From the Department of Nephrology (V.H., E.R., J.W.), University Hospital, University of Heidelberg, Heidelberg, Germany, and Institut de Génétique et de Biologie Moléculaire et Cellulaire (S.A.-S.), Illkirch-Strasbourg, France.

Correspondence to Dr Jürgen Wagner, Sektion Nephrologie, Medizinische Klinik, Bergheimerstrasse 56a, 69115 Heidelberg, Germany. E-mail juergen_wagner{at}med.uni-heidelberg.de

Abstract— Retinoids are derivatives of vitamin A and powerful inhibitors of cell proliferation and inflammation. Angiotensin II (Ang II) contributes to vascular lesions by promoting cell growth of vascular smooth muscle cells (VSMCs). Therefore, we examined whether retinoids interfere with the proproliferative actions of Ang II in VSMCs via AT1 receptor–dependent or activator protein-1 (AP-1)–dependent mechanisms. VSMCs express retinoid receptor proteins, ie, retinoic acid receptor (RAR) {alpha} and retinoid X receptor (RXR) {alpha}. Long-term exposure to 1 µmol/L all-trans retinoic acid (RA) dose-dependently inhibited Ang II–induced cell proliferation (P<0.005) as well as DNA and protein synthesis (P<0.001). All-trans RA blocked Ang II stimulation of transforming growth factor-ß1 mRNA (P<0.005). All-trans RA inhibition of vascular VSMC growth was mediated both via RAR- and RXR-dependent pathways, as shown by receptor-specific synthetic retinoids. Transfection experiments revealed that inhibition of AP-1–dependent gene transcription is one mechanism by which all-trans RA inhibits Ang II action. RAR{alpha} cotransfection enhanced the anti–AP-1 effects of all-trans RA dose-dependently. AP-1 activity was similarly inhibited by cotransfection with either RAR{alpha} or RXR{alpha}. Ang II–induced gene expression of c-fos was abrogated by all-trans RA treatment (P<0.005). In VSMCs, all-trans RA downregulated AT1 receptor mRNA (P<0.01) and reduced Bmax (P<0.001). All-trans RA repressed Ang II–stimulated AT1 receptor promoter activity. The all-trans RA inhibitory effect was abolished when the AP-1 consensus site on the AT1 receptor promoter was deleted. Our findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. The findings support the notion that retinoids may interfere with proliferative vascular disease.


Key Words: retinoic acid • angiotensin II • vascular smooth muscle cells • activator protein-1 • proliferation




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