Published online before print January 31, 2002, doi: 10.1161/01.ATV.0000012283.15789.67
© 2002 American Heart Association, Inc.
Vascular Biology |
Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models
From Laboratoire DIFEMA (L.V., C.S., F.M., J.-P.V., L.H.), UFR de Médecine et Pharmacie, Rouen, France; INSERM U553 (C.S.), Hôpital Saint Louis, Paris, France; Institut Gustave Roussy (P.O.), Villejuif, France; CNRS (Z.M.), IFR 2249, Villejuif, France; and Laboratoire de Biochimie and EMI 99-12 (J.S.), Hôtel-Dieu, Paris, France.
Reprint requests to Claudine Soria, Laboratoire DIFEMA, UFR de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen, France. E-mail claudine.soria{at}lrb.ap-hop-paris.fr
Cerivastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It inhibits the biosynthesis of cholesterol and its precursors: farnesyl pyrophosphate and geranylgeranyl pyrophosphate (GGPP), which are involved in Ras and RhoA cell signaling, respectively. Statins induce greater protection against vascular risk than that expected by cholesterol reduction. Therefore, cerivastatin could protect plaque against rupture, an important cause of ischemic events. In this study, the effect of cerivastatin was tested on angiogenesis because it participates in plaque progression and plaque destabilization. Cerivastatin inhibits in vitro the microvascular endothelial cell proliferation induced by growth factors, whereas it has no effect on unstimulated cells. This growth arrest occurs at the G1/S phase and is related to the increase of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. These effects are reversed by GGPP, suggesting that the inhibitory effect of cerivastatin is related to RhoA inactivation. This mechanism was confirmed by RhoA delocalization from cell membrane to cytoplasm and actin fiber depolymerization, which are also prevented by GGPP. It was also shown that RhoA-dependent inhibition of cell proliferation is mediated by the inhibition of focal adhesion kinase and Akt activations. Moreover, cerivastatin inhibits in vivo angiogenesis in matrigel and chick chorioallantoic membrane models. These results demonstrate the antiangiogenic activity of statins and suggest that it may contribute to their therapeutic benefits in the progression and acute manifestations of atherosclerosis.
Key Words: statins • angiogenesis inhibition • RhoA • vascular risk
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