title: Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells.
abstract: OBJECTIVE
  Adipocyte fatty acid-binding protein (A-FABP) is up-regulated in regenerated endothelial cells and modulates inflammatory responses in macrophages. Endothelial dysfunction accompanying regeneration is accelerated by hyperlipidaemia. Here, we investigate the contribution of A-FABP to the pathogenesis of endothelial dysfunction in the aorta of apolipoprotein E-deficient (ApoE(-/-) ) mice and in cultured human endothelial cells.
  
  
  METHODS
  A-FABP was measured in aortae of ApoE(-/-) mice and human endothelial cells by RT-PCR, immunostaining and immunoblotting. Total and phosphorylated forms of endothelial nitric oxide synthase (eNOS) were measured by immunoblotting. Changes in isometric tension were measured in rings of mice aortae
  
  
  RESULTS
  A-FABP was expressed in aortic endothelium of ApoE(-/-) mice aged 12 weeks and older, but not at 8 weeks or in C57 wild-type mice. Reduced endothelium-dependent relaxations to acetylcholine, UK14304 (selective α(2) -adrenoceptor agonist) and A23187 (calcium ionophore) and decreased protein presence of phosphorylated and total eNOS were observed in aortae of 18 week-old ApoE(-/-) mice compared with age-matched controls. A 6 week treatment with the A-FABP inhibitor, BMS309403, started in 12 week-old mice, improved endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations. The beneficial effect of BMS309403 on UK14304-induced relaxations was attenuated by Pertussis toxin. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production and was reversed by BMS309403.
  
  
  CONCLUSIONS
  Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro.
authors.affiliation: Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Mary Yk
authors.initials: MY
authors.lastname: Lee
authors.forename: Huiying
authors.initials: H
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D017667:Adipocytes / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D000001:Calcimycin / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D058647:Adrenergic alpha-2 Receptor Agonists; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; D001786:Blood Glucose; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D008055:Lipids; D011720:Pyrazoles; D009569:Nitric Oxide; D000001:Calcimycin; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine