Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC.
Fenofibrate improves endothelial function by lipid-lowering and anti-inflammatory effects. Additionally, fenofibrate has been demonstrated to upregulate endothelial nitric oxide synthase (eNOS). AMP-activated protein kinase (AMPK) has been reported to phosphorylate eNOS at Ser-1177 and stimulate vascular endothelium-derived nitric oxide (NO) production. We report here that fenofibrate activates AMPK and increases eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVEC). Incubation of HUVEC with fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase. Fenofibrate simultaneously increased eNOS phosphorylation and NO production. Inhibitors of protein kinase A and phosphatidylinositol 3-kinase failed to suppress the fenofibrate-induced eNOS phosphorylation. Neither bezafibrate nor WY-14643 activated AMPK in HUVEC. Furthermore, fenofibrate activated AMPK without requiring any transcriptional activities. These results indicate that fenofibrate stimulates eNOS phosphorylation and NO production through AMPK activation, which is suggested to be a novel characteristic of this agonist and unrelated to its effects on peroxisome proliferator-activated receptor alpha.
Murakami
Hisashi
H
Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
Murakami
Ryuichiro
R
Kambe
Fukushi
F
Cao
Xia
X
Takahashi
Ryotaro
R
Asai
Toru
T
Hirai
Toshihisa
T
Numaguchi
Yasushi
Y
Okumura
Kenji
K
Seo
Hisao
H
Murohara
Toyoaki
T
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D001629:Bezafibrate / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D014471:Umbilical Veins; D015854:Up-Regulation
D009097:Multienzyme Complexes; D047493:PPAR alpha; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C006253:pirinixic acid; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D011345:Fenofibrate; D001629:Bezafibrate