title: Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages.
abstract: Immunologic derangements in rheumatoid arthritis (RA) patients likely contribute to premature atherosclerotic cardiovascular disease (CVD). Traditional CVD risk factors do not reliably identify at-risk RA patients, probably because disease-associated mechanisms are not taken into account. The purpose of this study was to determine whether plasma from subjects with RA exhibits atheroma-promoting properties leading to disruption of cholesterol homeostasis in human monocytes/macrophages. Twenty-one healthy controls (HC) and 22 RA patients were enrolled in an IRB approved study at Winthrop University Hospital. Naïve THP-1 macrophages were exposed to plasma from each HC and RA patient. Following incubation, RNA and protein were isolated. QRT-PCR and Western blotting techniques were then used to measure expression of proteins responsible for cholesterol efflux (ATP binding cassette transporter (ABC)A1, ABCG1, 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low density lipoprotein receptor (LOX)-1, CXCL16). To confirm the pro-atherogenic effects of RA plasma on macrophages, foam cell formation was quantified. Results showed that RA plasma downregulates cholesterol efflux proteins and upregulates scavenger receptors CD36, LOX1 and CXCL16. These pro-atherogenic changes in gene expression in the presence of RA plasma are associated with augmented lipid accumulation and foam cell formation by THP-1 macrophages. RA plasma induces macrophage cholesterol overload. Demonstration of disrupted cholesterol homeostasis mediated by RA plasma provides further evidence of the involvement of the immune system in atherogenesis. Our data suggest that chronic exposure to RA plasma adversely affects the capacity of monocytes/macrophages in the arterial wall to metabolize cholesterol and maintain lipid homeostasis, thereby contributing to the development of premature atherosclerosis.
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, Mineola, NY 11501, USA.
authors.forename: Iryna
authors.initials: I
authors.lastname: Voloshyna
authors.forename: Sony
authors.initials: S
authors.lastname: Modayil
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Littlefield
authors.forename: Elise
authors.initials: E
authors.lastname: Belilos
authors.forename: Kristina
authors.initials: K
authors.lastname: Belostocki
authors.forename: Lois
authors.initials: L
authors.lastname: Bonetti
authors.forename: Gary
authors.initials: G
authors.lastname: Rosenblum
authors.forename: Steven E
authors.initials: SE
authors.lastname: Carsons
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000503:physiopathology*; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology*; D015153:Blotting, Western; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006706:Homeostasis; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D020543:Proteome / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D026901:Membrane Transport Proteins; D020543:Proteome; D002784:Cholesterol
keywords: Rheumatoid arthritis; atherosclerosis; cholesterol transport; macrophage