Direct vascular effects of HMG-CoA reductase inhibitors

Stefano Bellosta, Franco Bernini, Nicola Ferri, Pierangelo Quarato, Monica Canavesi, Lorenzo Arnaboldi, Remo Fumagalli, Rodolfo Paoletti, Alberto Corsini

Research output: Contribution to journalArticle

Abstract

Several studies have demonstrated that any beneficial effect of 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of the enzyme reaction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, hence effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently, we provided in vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification and endocytosis of modified lipoproteins. This in vitro inhibition was completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites - probably through a prenylated protein(s) - in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluvastatin-treated patients interfere with smooth muscle cell proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids, that could translate into a more significant prevention of cardiovascular disease.

Original languageEnglish
JournalAtherosclerosis
Volume137
Issue numberSUPPL.
DOIs
Publication statusPublished - Apr 1998

Keywords

  • AcLDL
  • Isoprenoids
  • Macrophages
  • SMC proliferation
  • Statins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Direct vascular effects of HMG-CoA reductase inhibitors'. Together they form a unique fingerprint.

  • Cite this

    Bellosta, S., Bernini, F., Ferri, N., Quarato, P., Canavesi, M., Arnaboldi, L., Fumagalli, R., Paoletti, R., & Corsini, A. (1998). Direct vascular effects of HMG-CoA reductase inhibitors. Atherosclerosis, 137(SUPPL.). https://doi.org/10.1016/S0021-9150(97)00319-5