Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
| Autor: | Elena Donetti, V. M. R. Soma, Alberto Corsini, Stefano Bellosta, Remo Fumagalli, P. Quarato, Rodolfo Paoletti, Franco Bernini |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
medicine.medical_specialty
Simvastatin Indoles Arteriosclerosis Muscle Smooth Vascular Fatty Acids Monounsaturated Rats Sprague-Dawley chemistry.chemical_compound Geranylgeraniol Cell Movement Internal medicine medicine Animals Pharmacology (medical) Lovastatin Enzyme Inhibitors Fluvastatin Cells Cultured Pravastatin biology Cholesterol business.industry Anticholesteremic Agents Macrophages Rats Endocrinology chemistry HMG-CoA reductase biology.protein lipids (amino acids peptides and proteins) Mevalonate pathway Rabbits Hydroxymethylglutaryl-CoA Reductase Inhibitors Cardiology and Cardiovascular Medicine business Cell Division medicine.drug |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0008-6312 |
| Popis: | 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 lipids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis. |
| Databáze: | OpenAIRE |
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