title: C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway.
abstract: OBJECTIVE
  Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN's metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown.
  
  
  RESULTS
  The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects.
  
  
  CONCLUSIONS
  We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, 4th Military Medical University, Xian, PR China.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Zheng
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Wei
authors.initials: W
authors.lastname: Yi
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Lopez
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Christopher
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peterson
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yu
authors.forename: Dinghua
authors.initials: D
authors.lastname: Yi
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D054419:Receptors, Adiponectin / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D052242:Adiponectin; C534692:CTRP9 protein, mouse; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases