Text
French
ID: <
10670/1.10.7202/000602ar>
Abstract
Statins lower circulating cholesterol by blocking the activity of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. However, statins possess pleiotropic properties that complement their cholesterol lowering effect, and makes this class of drugs very efficient to prevent, stabilize and perhaps regress coronary heart diseases through their direct action on the vascular wall. This includes correction of endothelial dysfunction (vasoreactivity, monocyte adhesion, haemostasis), improvement of plaque stability (decrease in MMP expression), reduction of monocyte infiltration, decrease in oxidation level, decrease in cell proliferation, and repair of ischemic tissues through the mobilization of endothelial progenitors. These pleiotropic effects are explained by the fact that statins inhibit the intracellular production of metabolites located downstream of mevalonate in the cholesterol pathway, such as isoprenoids (farnesyl pyrophosphate and geranylgeranylpyrophosphate). These hydrophobic metabolites allow the membrane anchorage of small G proteins (Ras and Rho) as well as the Gγ subunit of heterotrimeric G proteins, a post-translational step that is critical in the regulation of G protein signalling activity. Accordingly, the alteration of gene expression induced by statins can be reversed upon addition of these isoprenoids and not by cholesterol. The beneficial effects of statins are not restricted to the cardiovascular system; bone regeneration, cancer and HIV infection are also targeted. These drugs are therefore a promising tool, not only for the clinician but also for the biologist, allowing him/her to investigate the regulation of the gene expression that is controlled by the intracellular activity of membrane-anchored prenylated signalling proteins.