Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human endothelial cells

Br J Pharmacol. 2011 Apr;162(7):1564-76. doi: 10.1111/j.1476-5381.2010.01158.x.

Abstract

Background and purpose: 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.

Experimental approach: 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

Key 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 and implications: Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Adipocytes / metabolism
  • Adrenergic alpha-2 Receptor Agonists / pharmacology
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Biphenyl Compounds / pharmacology*
  • Blood Glucose / drug effects
  • Calcimycin / metabolism
  • Cells, Cultured
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Fatty Acid-Binding Proteins / antagonists & inhibitors
  • Fatty Acid-Binding Proteins / genetics
  • Fatty Acid-Binding Proteins / metabolism
  • Female
  • Humans
  • Insulin / blood
  • Lipids / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Pyrazoles / pharmacology*
  • Vasodilation / drug effects

Substances

  • 2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
  • Adrenergic alpha-2 Receptor Agonists
  • Apolipoproteins E
  • Biphenyl Compounds
  • Blood Glucose
  • Fatty Acid-Binding Proteins
  • Insulin
  • Lipids
  • Pyrazoles
  • Nitric Oxide
  • Calcimycin
  • Nitric Oxide Synthase Type III
  • Acetylcholine