Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells.
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.
Wang
Xinwen
X
Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
Liao
Dan
D
Lin
Peter H
PH
Yao
Qizhi
Q
Chen
Changyi
C
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
D000975:Antioxidants; D051242:Caveolin 1; D013481:Superoxides; D002784:Cholesterol; D019255:NADPH Oxidases