Pharmacological inhibition of adipocyte-fatty acid binding protein (A-FABP) improves endothelial function in male apolipoprotein E-knockout mice

Abstract

Adipocyte-fatty acid binding protein (A-FABP) modulates inflammatory responses in macrophages and may play a role in formation of foam cells and atherosclerotic plaques. A-FABP is markedly upregulated in regenerated porcine coronary arterial endothelial cells. The project were designed to investigate the presence (or not) of A-FABP as well as endothelial function at early stages of atherosclerosis in the aorta of 8, 12 and 18 weeks old male C57 apolipoprotein E-knockout (ApoE-/-) mice. The effect was determined by treatment with a selective A-FABP inhibitor, BMS 309403, in 12-weeks old ApoE-/- mice. A-FABP was detected by immunoflorescent staining in the endothelium of the aorta at 12, but not 8 weeks. In myograph experiments, the endothelium-dependent relaxations to acetylcholine and UK14304 (a selective α2-adrenoceptor agonist) were reduced significantly in the ApoE-/- mice at 8 and 12 weeks on, respectively, compared to those obtained in wild type mice. Relaxations to the calcium ionophore A23187 were diminished significantly only from 18 weeks. Treatment with the A-FABP inhibitor significantly improved the relaxation to acetylcholine and UK14304 but not that to A23187 without affecting the plasma lipid profile. In conclusion, A-FABP was detected in male atherosclerotic-prone ApoE-/- mice since the age of 12 weeks. Endothelial dysfunction was observed as early as at 8 weeks of age and deteriorated until 18 weeks, as judged from the reduced relaxations to acetylcholine, UK14304 and A23187. Endothelial dysfunction can be alleviated by treatment with an A-FABP inhibitor, suggesting that A-FABP may be a novel target for the treatment of endothelial dysfunction.