Fenofibrate promotes ischemia-induced revascularization through the adiponectin-dependent pathway.
Recent clinical trials demonstrated that PPARα agonist fenofibrate reduces cardiovascular events, including limb amputation in people with type 2 diabetes. Here, we investigated whether fenofibrate modulates the revascularization process in a mouse model of hindlimb ischemia. Treatment with fenofibrate led to acceleration of revascularization of ischemic hindlimb relative to the contralatereal limb in wild-type (WT) mice, as measured by laser Doppler blood flow and capillary density analyses. Treatment of WT mice with fenofibrate increased the serum levels of adiponectin, which has protective actions on the vasculature. Of importance, fenofibrate had no effects on the revascularization in ischemic limbs of adiponectin-deficient (APN-KO) mice. Fenofibrate stimulated the phosphorylation of AMPK and eNOS in the ischemic muscles in WT mice but not in APN-KO mice. AMPK inhibitor compound C suppressed fenofibrate-induced increase in limb perfusion and AMPK phosphorylation in ischemic muscle in WT mice without affecting adiponectin levels. NOS inhibitor l-NAME also blocked the increased blood flow of ischemic limbs in fenofibrate-treated WT mice. Our observations suggest that fenofibrate could promote revascularization in response to ischemia through adiponectin-dependent AMPK signaling.
Li
Ping
P
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shibata
Rei
R
Maruyama
Sonomi
S
Kondo
Megumi
M
Ohashi
Koji
K
Ouchi
Noriyuki
N
Murohara
Toyoaki
T
D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011345:Fenofibrate / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply* / Q000000981:diagnostic imaging; D007150:Immunohistochemistry; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008877:Middle East; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists* / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D018608:Ultrasonography, Doppler
D052242:Adiponectin; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D014280:Triglycerides; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; D000263:Adenylate Kinase; D011345:Fenofibrate; D019331:NG-Nitroarginine Methyl Ester