title: Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC.
abstract: 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.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Murakami
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Murakami
authors.forename: Fukushi
authors.initials: F
authors.lastname: Kambe
authors.forename: Xia
authors.initials: X
authors.lastname: Cao
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Asai
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Hirai
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Numaguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Okumura
authors.forename: Hisao
authors.initials: H
authors.lastname: Seo
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: 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
chemical_list: 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