Cholesterol is a structural component of the cell, indispensable for normal cellular function, but its excess often leads to abnormal proliferation, migration, inflammatory responses and/or cell death. To prevent cholesterol overload, ATP-binding cassette (ABC) transporters mediate cholesterol efflux from the cells to apolipoprotein A-I (ApoA-I) and to the ApoA-I-containing high-density lipoprotein (HDL)1-3. Maintaining efficient cholesterol efflux is essential for normal cellular function4-6. However, the role of cholesterol efflux in angiogenesis and the identity of its local regulators are poorly understood. Here we show that ApoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells (EC) to HDL and thereby regulates angiogenesis. AIBP/HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Remarkably, Aibp regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell autonomous regulator of zebrafish angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, while forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1/Abcg1-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1/Abcg1-deficient embryos. Our findings demonstrate that secreted AIBP positively regulates cholesterol efflux from EC and that effective cholesterol efflux is critical for proper angiogenesis.

Oxidative modification of LDL is an early pathological event in the development of atherosclerosis. Oxidation events such as malondialdehyde (MDA) formation may produce specific, immunogenic epitopes. Indeed, antibodies to MDA-derived epitopes are widely used in atherosclerosis research and have been demonstrated to enable cardiovascular imaging. In this study, we engineered a transgenic zebrafish with temperature-inducible expression of an EGFP-labeled single-chain human monoclonal antibody, IK17, which binds to MDA-LDL, and used optically transparent zebrafish larvae for imaging studies. IntroductionCholesterol-fed zebrafish represent a novel animal model in which to study the early events involved in vascular lipid accumulation and lipoprotein oxidation (1, 2). This zebrafish model has several unique advantages. The optical transparency of zebrafish larvae enables high-resolution monitoring of vascular pathology in live animals. Colony maintenance is cost-effective, and many embryos can be produced from a single mating. Further, it is relatively easy to establish new transgenic zebrafish lines harboring fluorescent proteins. Importantly, our recent work established that feeding zebrafish a high-cholesterol diet (HCD) resulted in hypercholesterolemia, vascular lipid accumulation, myeloid cell recruitment, and other pathological processes characteristic of early atherogenesis in mammals (1). HCD-fed zebrafish had remarkably high levels of oxidized lipoproteins and specific oxidized phospholipid and cholesteryl ester moieties as measured by binding of oxidation-specific antibodies and by mass spectrometry (1, 2). These observations suggest that there is accelerated lipid oxidation in HCD-fed zebrafish.Oxidative modification of LDL is widely believed to drive the initial formation and progression of atherosclerotic lesions in humans

At present there are conflicting results from studies investigating the role of corticosteroids in inhibiting airway remodeling in asthma. We have used a mouse model to determine whether administration of corticosteroids prevents the development of allergen-induced structural features of airway remodeling. Mice treated with corticosteroids were subjected to repetitive ovalbumin (OVA) challenge for 3 mo, at which time levels of peribronchial fibrosis and the thickness of the peribronchial smooth muscle layer were assessed by immunohistology, levels of transforming growth factor (TGF)-beta1 by ELISA, and the number of alpha-smooth muscle actin+/Col-1+ peribronchial myofibroblasts by immunohistochemistry. Corticosteroids significantly reduced allergen-induced increases in peribronchial collagen deposition and levels of total lung collagen but did not reduce allergen-induced increases in the thickness of the peribronchial smooth muscle layer. Levels of lung TGF-beta1 were significantly reduced in mice treated with systemic corticosteroids, and this was associated with a significant decrease in the number of peribronchial inflammatory cells that expressed TGF-beta1, including eosinophils and mononuclear cells. Corticosteroids also significantly reduced the number of peribronchial myofibroblasts. Overall, these studies demonstrate that administration of corticosteroids significantly reduces levels of allergen-induced peribronchial fibrosis. The reduction in peribronchial fibrosis mediated by corticosteroids is likely to be due to several mechanisms including inhibition of expression of TGF-beta1, a reduction in the number of peribronchial inflammatory cells expressing TGF-beta1 (eosinophils, macrophages), as well as by corticosteroids reducing the accumulation of peribronchial myofibroblasts that contribute to collagen expression.

ObjectivesEndonasal dacryocystorhinostomy (DCR) is a well-established treatment method in patients with nasolacrimal duct obstruction. However, there are a few reports about the overall management of failed endonasal DCR. We investigated the causes and management strategies of failed endonasal DCR.MethodsThis retrospective review included 61 patients (61 eyes) who had undergone revision surgery by the same surgeon after failed endonasal DCR between January 2008 and December 2012. The appropriate revision method was determined after analysis of the etiology of failure by the fluorescein dye disappearance test, nasal endoscopy, lacrimal irrigation, and probing. The criteria for success of the revision surgery were defined by the passage of fluid without resistance upon lacrimal irrigation and normalization of the tear meniscus height.ResultsThe mean duration between the primary endonasal DCR and revision surgery was 15.3 months. The average follow-up period after revision surgery was 12.2 months. The most common cause of endoscopic revision surgery was membranous obstruction. Endoscopic revision surgery was performed in 48 patients, while lacrimal silicone tube intubation under endoscopy was performed in 13 patients. The most common indication for lacrimal silicone tube intubation was functional epiphora. The overall success rate of the revision surgery was 89%.ConclusionThe most common cause of failed endonasal DCR was membranous obstruction. When patients with failed endonasal DCR presented at the clinic, it is important to identify the cause of the failure. Revision surgery could increase the final success rate of endonasal DCR.