© 2001 American Heart Association, Inc.
Molecular Medicine |
Retinoids Inhibit the Actions of Angiotensin II on Vascular Smooth Muscle Cells
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)
and retinoid X receptor (RXR) . 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 cotransfection enhanced the anti–AP-1 effects of
all-trans RA dose-dependently.
AP-1 activity was similarly inhibited by cotransfection with either
RAR or RXR. 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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