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Results demonstrate that oleic acid and other long chain saturated and unsaturated free fatty acids increase lipid mobilities and cholesterol transfer rates in large unilamellar vesicles containing phospholipid and cholesterol. Further, the large unilamellar vesicles containing only sphingomyelin show decreased transfer rates but in the presence of oleic acid the rate is increases by 1.3-fold.

The coxsackievirus and adenovirus receptor (CAR), in addition to serving as viral receptor, is a component of tight junctions and plays an important role in tissue homeostasis. Defects in the cystic fibrosis transmembrane regulator (CFTR) in lung epithelial cells are linked to inflammation and susceptibility for respiratory tract infections. Here, we demonstrate that CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis airway epithelial cells. Inhibition of CFTR or histone deacetylase (HDAC) enhanced CAR expression while CFTR overexpression or restoration of the diminished HDAC activity in cystic fibrosis cells reduced CAR expression. This connects the CFTR to CAR expression and infectivity with adenovirus through HDAC. [ABSTRACT FROM AUTHOR]

The inflammatory milieu in the respiratory tract in cystic fibrosis (CF) has been linked to the defective expression of the cystic transmembrane regulator (CFTR) in epithelial cells. Alveolar macrophages (AM), important contibutors to inflammatory responses in the lung, also express CFTR. The present study analyzes the phenotype of human AM with silenced CFTR. Expression of CFTR mRNA and the immature form of the CFTR protein decreased 100-fold and 5.2-fold, respectively, in AM transfected with a CFTR specific siRNA (CFTR-siRNA) compared to controls. Reduction of CFTR expression in AM resulted in increased secretion of IL-8, increased phosphorylation of NF-κB, a positive regulator of IL-8 expression, and decreased expression of IkB-α, the inhibitory protein of NF-κB activation. AM with silenced CFTR expression also showed increased apoptosis. We hypothesized that caveolin-1 (Cav1), a membrane protein that is colocalized with CFTR in lipid rafts and that is related to inflammation and apoptosis in macrophages, may be affected by decreased CFTR expression. Messenger RNA and protein levels of Cav1 were increased in AM with silenced CFTR. Expression and transcriptional activity of sterol regulatory element binding protein (SREBP), a negative transcriptional regulator of Cav1, was decreased in AM with silenced CFTR, but total and free cholesterol mass did not change. These findings indicate that silencing of CFTR in human AM results in an inflammatory phenotype and apoptosis, which is associated to SREBP-mediated regulation of Cav1. [ABSTRACT FROM AUTHOR]

Plasma LDL levels and atherosclerosis both increase on a saturated fat-rich (SAT) diet. LDL cholesterol delivery to tissue may occur via uptake of the LDL particles or via selective uptake (SU), wherein cholesteryl ester (CE) enters cells without concomitant whole-particle uptake. It is not known how dietary fats might directly affect arterial LDL-CE uptake and whether SU is involved. Thus, mice that are relatively atherosclerosis resistant (C57BL/6) or susceptible to atherosclerosis (apoE-/-) were fed a chow or SAT diet and injected with double radiolabeled or fluorescent-labeled human LDL to independently trace LDL-CE core and whole-particle uptake, respectively. Our results show that a SAT diet increased contributions of SU to total arterial LDL-CE delivery in C57BL/6 and apoE-/- mice. The SAT diet increased plasma fatty acid and cholesterol levels; cholesterol, but not fatty acid, levels correlated with SU, as did the degree of atherosclerosis. Increased SU did not correlate with arterial scavenger receptor class B type I levels but paralleled increased lipoprotein lipase (LPL) levels and LPL distribution in the arterial wall. These studies suggest that arterial LDL-CE delivery via SU can be an important mechanism in vivo and that dietary influences on arterial LPL levels and atherogenesis modulate arterial LDL-CE delivery, cholesterol deposition, and SU. [ABSTRACT FROM AUTHOR]

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.