Fenofibrate inhibits angiogenesis in vitro and in vivo.
Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-alpha activator, used as a normolipidemic agent, is thought to offer additional beneficial effects in atherosclerosis. Since angiogenesis is involved in plaque progression, hemorrhage, and instability, the main causes of ischemic events, this study was designed to evaluate the action of fenofibrate on angiogenesis. Our results show that fenofibrate (i) inhibits endothelial cell proliferation induced by angiogenic factors, followed at high concentrations by an increase in apoptosis, (ii) inhibits endothelial cell migration in a healing wound model, (iii) inhibits capillary tube formation in vitro, and (iv) inhibits angiogenesis in vivo. Concerning the mechanism of action, the inhibition of endothelial cell migration by fenofibrate can be explained by a disorganization of the actin cytoskeleton. At the molecular level, fenofibrate markedly decreased basic fibroblast growth factor-induced Akt activation and cyclooxygenase 2 gene expression. This inhibition of angiogenesis could participate in the beneficial effect of fenofibrate in atherosclerosis.
Varet
J
J
Laboratoire DIFEMA, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen, France.
Vincent
L
L
Mirshahi
P
P
Pille
J V
JV
Legrand
E
E
Opolon
P
P
Mishal
Z
Z
Soria
J
J
Li
H
H
Soria
C
C
D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000254:growth & development; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2; D020405:Dermis / Q000187:drug effects / Q000254:growth & development; D004727:Endothelium / Q000187:drug effects / Q000254:growth & development; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt
D000199:Actins; D000960:Hypolipidemic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011345:Fenofibrate