Non-Lipid-Related Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

Abstract

With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lip-ids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.

Inflammation, Homocysteine, Pyridoxal-5-phosphate and Lipids in Patients with Coronary Artery Disease before and Six Months after Coronary Angioplasty Followed by Stent Implantation

“…These drugs arc used for the treatment of hypercholesterolemia (21,33), and clinical trials have demonstrated that they can induce regression of vascular atherosclerosis as well as reduce cardiovascular morbidity and mortality in patients with CAD and other cardiovascular diseases (21,32,34,35). Slight and/or statistically significant decrease of cholesterol, HDL and LDL as well as CHOL/PL observed 6 months after the treatment partly agrees with data in literature.…”

Statin Therapy Interacts With Cytomegalovirus Seropositivity and High C-Reactive Protein in Reducing Mortality Among Patients With Angiographically Significant Coronary Disease

“…In some bench studies, statins have been shown to possess immune modifying 17,18 and antiinflammatory effects. 17,19,20 Recent clinical studies show a differential effect of statins on CRP-associated risk, supporting this antiinflammatory hypothesis. 6,21 Although statin therapy appears to reduce CRP-related events, no study has evaluated the effect of statins on infection-related events.…”

“…6,15,16,21 In addition to lowering cholesterol, statins have been postulated to have a variety of other beneficial effects, including antiinflammatory effects. 17,19,20 Several studies suggest that statins reduce events associated with elevated CRP 6,21 and that they reduce plasma concentrations of CRP. 22 These findings reveal a strong potential for the use of statins in the treatment of CRP-related risk.…”

Statins and Blockers of the Renin-Angiotensin System

“…Only the presence of geranylgeraniol or farnesol in the medium containing statins leads to an almost-complete restoration of the mitogenic response. 25 Farnesol and geranylgeraniol interact with the hydrophilic Ras protein family and become covalently linked. The acquisition of lipophilicity by the complex allows the interaction of Ras proteins with cellular membranes.…”