Fenofibrate Enhances Neovascularization in a Murine Ischemic Hindlimb Model

Abstract

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.

Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway

“…In agreement with our data, fenofibrate treatment leads to an increase in revascularization in ischemic hindlimbs (14). Likewise, another PPAR␣ agonist, WY-14643, promotes neovascular growth in a model of angiogenesis in the mouse cornea (5).…”

“…A recent analysis of the FIELD study has shown that fenofibrate suppresses the occurrence of a lower limb amputation in patients with type 2 diabetes (28). Consistent with these clinical observations, several experimental studies have indicated that, in addition to its lipid-lowering effect, fenofibrate has beneficial effects on the vascular wall, including improvement of endothelial function and revascularization (2,14,37). However, the precise mechanism of how fenofibrate regulates vascular function is incompletely understood.…”

“…Blood flow recovery in ischemic hindlimb appeared to be accelerated in the fenofibrate-treated WT mice compared with untreated mice. Quantitative analysis of hindlimb perfusion showed that treatment with fenofibrate significantly increased the limb flow of ischemic muscle in WT mice on postoperative days 3,7,14,21, and 28 (Fig. 1B).…”

“…We measured hindlimb blood flow using a laser Doppler blood flowmetry (LDBF; MoorLDI, Moor Instrument, Devon, UK), as described previously (22,33). Before and on postoperative days 0, 3,7,14,21, and 28, we performed LDBF analysis over the legs and feet. After scanning, storage images were analyzed to quantify blood flow, and mean LDBF values of the ischemic and nonischemic limbs were calculated.…”

Targeting Nuclear Hormone Receptors: PPARαAgonists as Potential Disease-Modifying Drugs for Rheumatoid Arthritis

“…Other research has demonstrated antiangiogenic effects of fibrates leading to suppressed tumor growth [40]. In contrast, fenofibrate enhanced neovascularization in a murine hind-limb ischemia model [41] and in a murine corneal model of angiogenesis [42]. …”