title: Implication of AMP-activated protein kinase in transient receptor potential vanilloid type 1-mediated activation of endothelial nitric oxide synthase.
abstract: We investigated whether AMP-activated protein kinase (AMPK), a multi-functional regulator of energy homeostasis, is involved in transient receptor potential vanilloid type 1 (TRPV1)-mediated activation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) and mice. In ECs, treatment with evodiamine, the activator of TRPV1, increased the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and eNOS, as revealed by western blot analysis. Inhibition of AMPK activation by compound C or dominant-negative AMPK mutant abrogated the evodiamine-induced increase in phosphorylation of AMPK and eNOS and NO bioavailability, as well as tube formation in ECs. Immunoprecipitation and two-hybrid analysis demonstrated that AMPK mediated the evodiamine-induced increase in the formation of a TRPV1-eNOS complex. Additionally, TRPV1 activation by evodiamine increased the phosphorylation of AMPK and eNOS in aortas of wild-type mice but did not activate eNOS in aortas of TRPV1-deficient mice. In mice, inhibition of AMPK activation by compound C markedly decreased evodiamine-evoked angiogenesis in Matrigel plugs and in a hind-limb ischemia model. Moreover, evodiamine-induced phosphorylation of AMPK and eNOS in aortas of apolipoprotein E deficient (ApoE(-/-)) mice was abrogated in TRPV1-deficient ApoE(-/-) mice. In conclusion, TRPV1 activation may trigger AMPK-dependent signaling, which leads to enhanced activation of AMPK and eNOS and retarded development of atherosclerosis.
authors.affiliation: Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Li-Chieh
authors.initials: LC
authors.lastname: Ching
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.forename: Kuo-Hui
authors.initials: KH
authors.lastname: Su
authors.forename: Hsin-Han
authors.initials: HH
authors.lastname: Hou
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D001808:Blood Vessels / Q000187:drug effects; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007797:Laminin; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D011509:Proteoglycans; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011799:Quinazolines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C059485:matrigel; D009569:Nitric Oxide; D003094:Collagen; C049639:evodiamine; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases