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 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. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.link_to_subscribed_fulltex

Generation and specification of unique neuronal sub-types: lessons from Drosophila neuropeptide neurons

The central nervous system (CNS) contains a daunting diversity of neuronal cell types. One of the major challenges of developmental neurobiology is to understand the regulatory mechanisms underlying this vast complexity. Studies in the Drosophila melanogaster (Drosophila) model system has contributed greatly to our understanding of neuronal cell sub-type specification, and the majority of mechanisms and genes identified in this system has proved to be of great value, and often more or less directly transferable to studies of mammalian neuro-development. In Drosophila, studies of the developmental generation of numerous different neuropeptide neurons have been highly informative, since these neurons are generated in a highly restricted and reproducible manner. In addition, neuropeptides are expressed at high levels and their regulatory regions have proven comparatively condensed, facilitating the generation of a multitude of antibodies and transgenic markers. Here, we first provide a general background to Drosophila CNS development. Then, we focus in more detail on various well studied neuropeptide neurons identified in this system, and describe what has been learned regarding the generation and differentiation of these highly unique neuronal sub-types. We intend this review to provide an overview of the variety of mechanisms that operate throughout the developmental period to generate highly unique neuronal sub-types. Finally, we conclude with some general remarks and perspectives regarding neuronal sub-type specification in general