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

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 α₂‐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.

DOI: 10.1111/j.1476-5381.2010.01158.x

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