title: Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction.
abstract: BACKGROUND
  Adipocyte-derived hormones may represent a mechanism linking insulin resistance to cardiovascular disease. In the present study, we evaluated the direct effects of resistin, a novel adipocyte-derived hormone, on endothelial activation.
  
  
  RESULTS
  Endothelial cells (ECs) were incubated with human recombinant resistin (10 to 100 ng/ML, 24 hours), and endothelin-1 (ET-1) release, ET-1 mRNA expression, and nitric oxide (NO) production were assessed. Transient transfection assays were used to evaluate the effects of resistin on transcription of human ET-1 gene promoter. Furthermore, the effects of resistin on AP-1-mutated ET-1 promoter were evaluated. The effects of resistin on expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) were studied in addition to CD40 receptor, CD40 ligand-induced MCP-1 expression, and tumor necrosis factor receptor-associated factor-3 (TRAF3), an inhibitor of CD40 signaling. Incubation of ECs with resistin resulted in an increase in ET-1 release and ET-1 mRNA expression, with no change in NO production. Whereas treatment with resistin resulted in an increase in ET-1 promoter activity, the AP-1-mutated promoter was inactive after resistin stimulation. Additionally, resistin-treated cells showed increased expression of VCAM-1 and MCP-1, with concomitant reductions in TRAF-3 expression. Resistin did not alter CD40 receptor expression; however, increased CD40 ligand induced MCP-1 production.
  
  
  CONCLUSIONS
  The novel adipokine resistin exerts direct effects to promote EC activation by promoting ET-1 release, in part by inducing ET-1 promoter activity via the AP-1 site. Furthermore, resistin upregulates adhesion molecules and chemokines and downregulates TRAF-3, an inhibitor of CD40 ligand signaling. In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome.
authors.affiliation: Division of Cardiac Surgery, Toronto General Hospital, 14EN-215, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. subodh.verma@sympatico.ca
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Donald A G
authors.initials: DA
authors.lastname: Mickle
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D023201:CD40 Ligand / Q000494:pharmacology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006729:Hormones, Ectopic / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009569:Nitric Oxide / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D052243:Resistin; D048008:TNF Receptor-Associated Factor 3; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D019332:Endothelin-1; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C499624:RETN protein, human; C486574:RETNLB protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D052243:Resistin; D048008:TNF Receptor-Associated Factor 3; D019010:Vascular Cell Adhesion Molecule-1; D023201:CD40 Ligand; D009569:Nitric Oxide