Insights in the molecular mechanisms of the anti-angiogenic effect of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of coronary event by cholesterollowering dependent and independent mechanisms. We have already described that the inhibitory effect of cerivastatin on angiogenesis contribute to the cholesterol-independent beneficial effect and was due to the inhibition of the cell signaling cascade RhoA/FAK/Akt. In this study, new insights in the molecular mechanism of action were provided. It indicates an inhibition of exposure of alpha V beta 3 integrin on cell membrane and a modification of gene expression. The inhibition of angiogenesis could be related to 1) an increase in genes involved in the inhibition of cell proliferation (p19(INK4), p21(Waf/Cip1),Wnt-5a), the inhibition of cell migration (Rho-GDI 1, alpha E-catenin) and 2) a downregulation of genes involved in angiogenesis (PAI-1, Vitronectin, HoxD3, Notch4) or in cell invasion (Semaphorin E). In addition, DNA repair protein genes (MLH1, XRCC1) were increased. This study may indicate new biological interest of genes involved in angiogenesis control.
Vincent
Loïc
L
Laboratoire DIFEMA, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen, France.
Albanese
Patricia
P
Bompais
Heidi
H
Uzan
Georges
G
Vannier
Jean Pierre
JP
Steg
Philippe Gabriel
PG
Soria
Jeannette
J
Soria
Claudine
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D039302:Integrin alphaVbeta3 / Q000235:genetics; D016023:Integrins / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D039302:Integrin alphaVbeta3; D016023:Integrins; D011725:Pyridines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C086276:cerivastatin; D020742:rhoA GTP-Binding Protein