Statin-Mediated Inhibition of Rho

Abstract

See related article, pages 1014–1021 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). 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. GTPase activating proteins (GAP) promote GTP hydrolysis by RhoA and thus RhoA inactivation. GDP-bound RhoA interacts with guanine dissociation inhibitors (GDI) through the geranylgeranyl tail. GDI stabilizes the inactive form of RhoA. …