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-glutaryl-coenzyme A reductase (statins) can play a role in protection against vascular risk, which is independent of cholesterol reduction. It could act by inhibiting the synthesis of isoprenoids (farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP)), which are respectively essential for membrane attachment and biological activity of GTPases Ras and RhoA. This study demonstrates that a statin (cerivastatin) inhibits angiogenesis. This effect 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, was also observed. This effect is rather due to Ras inhibition as it was reversed by FPP. This anti-angiogenic activity could explain the beneficial effect of statins on atherosclerosis and on cancer prevention as shown by clinical studies.
Vincent
L
L
Laboratire DIFEMA, UFRde Médecine et de Pharmacie de Rouen, France.
Chen
W
W
Hong
L
L
Mirshahi
F
F
Mishal
Z
Z
Mirshahi-Khorassani
T
T
Vannier
J P
JP
Soria
J
J
Soria
C
C
D000199:Actins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011108:Polymers / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D016228:Endothelial Growth Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008222:Lymphokines; C508351:OSM protein, human; D010455:Peptides; D011106:Polyisoprenyl Phosphates; D011108:Polymers; D011725:Pyridines; D012333:RNA, Messenger; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D053683:Oncostatin M; C004808:farnesyl pyrophosphate; C086276:cerivastatin; D020778:Matrix Metalloproteinase 2; D020742:rhoA GTP-Binding Protein