Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect

Recent studies have suggested that inhibitors of 3-hydroxy-3-methyl-glutary l-coenzyme A reductase (statins) can play a role in protection against vasc ular risk, which is independent of cholesterol reduction. It could act by i nhibiting the synthesis of isoprenoids (farnesylpyrophosphate (FPP) and ger anylgeranylpyrophosphate (GGPP)), which are respectively essential for memb rane attachment and biological activity of GTPases Ras and RhoA. This study demonstrates that a statin (cerivastatin) inhibits angiogenesis, This effe ct was due to a decrease in endothelial cell locomotion which was reversed by GGPP, It was mainly related to delocalization of RhoA from cell membrane to cytoplasm, responsible for the disorganization of actin stress fibers. Furthermore, a decrease in MMP-2 secretion, involved in cell invasion, mas also observed. This effect is rather due to Ras inhibition as it was revers ed by FPP, This antiangiogenic activity could explain the beneficial effect of statins on atherosclerosis and on cancer prevention as shown by clinica l studies. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.