Fenofibrate enhances neovascularization in a murine ischemic hindlimb model.
Fenofibrate have been illustrated to stimulate nitric oxide (NO) pathway, which plays pivotal roles in neovascularization. Here, we evaluated the effect of fenofibrate on neovascularization using a murine ischemic hindlimb model. C57BL/6J mice were treated with fenofibrate and/or NG-nitro-l-arginine methyl ester hydrochloride (l-NAME) for 28 days after ischemia operation. We exploited a concentration of L-NAME that did not affect blood pressure levels but suppress NO activity. Limb blood perfusion and capillary density in ischemic limb, serum NO levels, and aortic NOS activity were significantly increased by fenofibrate treatment when compared with the untreatment group. And, these effects were abolished by coadministration of L-NAME. Fenofibrate treatment significantly lowered serum triglyceride levels. Cotreatment of L-NAME did not inhibit serum triglyceride level, lowering effect of fenofibrate. These results suggested that the lowering in serum triglyceride levels is not involved in the improvement of neovascularization. In an in vitro experiment, fenofibrate stimulated NOS activity in human umbilical vein endothelial cells. Also, fenofibrate stimulated in vitro angiogenesis, and this effect was abolished by coincubation with L-NAME. In conclusions, fenofibrate enhanced neovascularization in a murine hindlimb ischemia model. The mechanism is most likely through activation of NO pathway in endothelial cells.
Katayama
Akira
A
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan.
Yamamoto
Yasutaka
Y
Tanaka
Kohei
K
Matsubara
Koichi
K
Sugitani
Miyoko
M
Fujihara
Satomi
S
Harada
Shingo
S
Kaetsu
Yasuhiro
Y
Yoshida
Akio
A
Hisatome
Ichiro
I
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006614:Hindlimb / Q000098:blood supply*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D014280:Triglycerides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011345:Fenofibrate; D019331:NG-Nitroarginine Methyl Ester