title: Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.
abstract: We previously reported that HIV protease inhibitor, ritonavir, could inhibit cholesterol efflux and induce endothelial dysfunction. In this study, we further determined the effects and molecular mechanisms of a clinically relevant combination of highly active antiretroviral therapy (HAART) drugs on in vitro cholesterol efflux from human macrophage-derived foam cells. Foam cells derived from human monocyte cell line (THP-1) and periphery blood mononuclear cells (PBMCs) treated with HAART drugs including stavudine, didanosine and indinavir individually or in combination of three drugs (3-plex), followed by the initiation of cholesterol efflux with apolipoprotein A-I (apoA-I). Clinically relevant concentrations of HAART 3-plex significantly reduced cholesterol efflux in foam cells derived from THP-1 and PBMCs. HAART 3-plex significantly reduced the intracellular cholesterol transport molecule caveolin-1, whereas it increased superoxide anion production in THP-1 foam cells as compared with controls. Furthermore, mitochondrial membrane potential was significantly reduced, whereas the expression of NADPH oxidase subunit p67(phox) was increased in HAART 3-plex-treated macrophages. Consequently, antioxidants including ginsenosides Rb1 and Rg1, S-allyl cysteine sulphoxide (SACS), simvastatin (SVT) and vitamin E significantly abolished HAART 3-plex-induced inhibition of cholesterol efflux. Therefore, HAART drugs significantly inhibit cholesterol efflux from human macrophage-derived foam cells through downregulation of caveolin-1 and increase of oxidative stress.
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.forename: Dan
authors.initials: D
authors.lastname: Liao
authors.forename: Peter H
authors.initials: PH
authors.lastname: Lin
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051242:Caveolin 1; D013481:Superoxides; D002784:Cholesterol; D019255:NADPH Oxidases