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Vol. 59, Issue 3, 646-654, March 2001
Medizinische Klinik und Poliklinik, Innere Medizin III,
Universitätskliniken des Saarlandes, Homburg/Saar, Germany (S.W.,
U.L., K.M., C.K., M.B., G.N.); and Klinik III für Innere Medizin
(A.T.B) and Zentrum für Physiologie und Pathophysiologie (H.S.),
Universität zu Köln, Cologne, Germany
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins)
may exert pleiotropic effects on vascular cells independent of lowering
plasma cholesterol. To elucidate the molecular mechanisms involved in
these effects, we investigated the impact of statins on production of
reactive oxygen species (ROS) in rat aortic vascular smooth muscle
cells (VSMC). Exposure of VSMC to angiotensin II caused production of
ROS via angiotensin AT1 receptor activation. Pretreatment with
atorvastatin inhibited angiotensin II-induced ROS production.
Atorvastatin decreased AT1 receptor mRNA levels in a time- and
concentration-dependent manner and consistently reduced AT1 receptor
density. L-Mevalonate but not hydroxy-cholesterol reversed
the inhibitory effect of atorvastatin on AT1 receptor transcript
levels. Inhibition of geranylgeranyl-transferase but not of
farnesyl-transferase mimicked the effect of atorvastatin on AT1
receptor gene expression. Atorvastatin did not decrease AT1 receptor
gene transcription but did reduce the half-life of the AT1 receptor
mRNA. AT1 receptor activation by angiotensin II increased the
expression of the GTPase rac1, enhanced rac1 GTP-binding activity, and
increased the geranylgeranyl-dependent translocation of rac1 to the
cell membrane. In contrast, statins inhibited rac1 activity and
membrane translocation. Consequently, specific inhibition of rac1 with
Clostridium sordellii lethal toxin blocked angiotensin
II-induced production of free radicals. Finally, treatment of rats with
atorvastatin caused down-regulation of aortic AT1 receptor mRNA
expression and reduced aortic superoxide production in vivo.
Cholesterol-independent down-regulation of AT1 receptor gene expression
and inhibition of rac1, leading to decreased ROS production,
demonstrates a novel regulatory mechanism of statins that may
contribute to the beneficial effects of these drugs beyond lowering of
plasma cholesterol.
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