Published Online
on September 16, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on May 28, 2004
Accepted on August 5, 2004

Effects of Statins on Endothelium and Signaling Mechanisms

Matthias Endres MD^* and Ulrich Laufs MD

From the Klinik und Poliklinik für Neurologie (M.E.), Charité, Humboldt-Universität Berlin, Germany; and the Klinik für Kardiologie (U.L.), Universität des Saarlandes, Homburg, Germany,

^* To whom correspondence should be addressed. E-mail: Matthias.endres{at}charite.de.

Abstract--Endothelium dysfunction may result from increased production of reactive oxygen species and decreased availability of nitric oxide. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, statins) exert cholesterol-independent vasoprotective effects that are mediated, in part, through the inhibition of small G-proteins Rho and Rac. Rho negatively regulates endothelial nitric oxide synthase and Rac contributes to NAD(P)H-oxidase activation and superoxide production. Statins inhibit both Rho and Rac GTPase activity via inhibition of geranylgeranylation, which confers endothelial nitric oxide synthase upregulation and decreases superoxide production, respectively. Sudden discontinuation of statin therapy may have negative effects. Withdrawal of statin treatment leads to an overshoot activation of Rho and Rac with dramatic effects on nitric oxide bioavailability, NAD(P)H-oxidase activity, and superoxide production.

Key words: acute care

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