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(Circulation Research. 2005;96:927.)
© 2005 American Heart Association, Inc.

Editorials

Statin-Mediated Inhibition of Rho

Only to Get More NO?

Ralf P. Brandes

From the Institut für Kardiovaskuläre Physiologie, J.W. Goethe-Universität, Frankfurt am Main, Germany

Correspondence to Ralf P. Brandes, MD, Institut für Kardiovaskuläre Physiologie, Fachbereich Medizin, J.W. Goethe-Universität, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. E-mail r.brandes@em.uni-frankfurt.de

See related article, pages 1014–1021

Key Words: statins • nitric oxide • endothelium • GTPases • hypertension

An extract of the first 250 words of the full text is provided, because this article has no abstract.

HMG-CoA reductase inhibitors (statins) are more than just cholesterol-lowering drugs. The effects of statins in the cardiovascular system include, among others, the improvement of endothelium-dependent relaxation, a reduction in the progression of arteriosclerosis, an antihypertensive effect and beneficial actions on cardiac function.¹ The pleiotropic actions even extend beyond the cardiovascular system and have been suggested to attenuate the progression of osteoporosis, reduce the incidence or severity of dementia, type II diabetes, allograft organ rejection and inflammation.¹

Some of the effects of statins are attributed to interactions of the drugs with cell surface receptors, effects on cytochrome P450 monoxygenases and actions on the PI3-kinase pathway. The most important mechanism for the pleiotropic effects, however, is the inhibition of small GTPases.² Small GTPases, which include proteins of the Ras and Rho families, mediate essential cellular signals required for proliferation, migration, and gene expression.³

To elicit their biological effects, small GTPases have to be anchored in the plasma membrane by an isoprenoid tail. Isoprenoids are intermediates of the cholesterol de novo synthesis. By inhibiting the key enzyme of the cholesterol de novo synthesis, the HMG-CoA reductase, statins deplete the cell of these lipids and thus elicit the retention of small GTPases in the cytosol, where they cannot exert their biological actions² (Figure 1).

View larger version (50K): [in this window] [in a new window]   Figure 1. Activation of RhoA geranyltransferase (GTF) catalyzes geranylgeranylation of RhoA with geranylgeranylpyrophosphate, thereby allowing anchoring of RhoA in the membrane. Guanine exchange factors (GEF) activate GDP/GTP exchange of RhoA, In the GTP-bound state RhoA is functionally active. . . . [Full Text of this Article]

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Circ. Res. 2005 96: 1014-1021. [Abstract] [Full Text] [PDF]

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