Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells.
Clinical use of human immunodeficiency virus protease inhibitors such as ritonavir may be associated with cardiovascular disease. The objective of this study was to determine the effects and molecular mechanisms of ritonavir on cholesterol efflux from human macrophage-derived foam cells, which is a critical factor of atherogenesis. Human THP-1 monocytes and peripheral blood mononuclear cells were preincubated with acetylated low-density lipoprotein and [(3)H]cholesterol to form foam cells, which were then treated with apolipoprotein A-I for cholesterol efflux assay. A clinically relevant concentration of ritonavir (15 mumol/L) significantly reduced cholesterol efflux from THP-1 and peripheral blood mononuclear cells to apolipoprotein A-I by 30 and 29%, respectively, as compared with controls. In addition, ritonavir significantly decreased the expression of scavenger receptor B1 and caveolin-1, whereas it significantly increased superoxide anion production and activated extracellular signal-regulated kinase (ERK) 1/2 in macrophages. Mitochondrial membrane potential was significantly reduced, whereas NADPH oxidase subunits were increased in ritonavir-treated macrophages. Consequently, the antioxidant seleno-l-methionine, the specific ERK1/2 inhibitor PD98059, or infection of a recombinant adenovirus encoding the dominant-negative form of ERK2 effectively blocked ritonavir-induced decrease of cholesterol efflux. Therefore, human immunodeficiency virus protease inhibitor ritonavir significantly inhibits cholesterol efflux from macrophages, which may be mediated by mitochondrial dysfunction, oxidative stress, ERK1/2 activation, and down-regulation of scavenger receptor B1 and caveolin-1.
Wang
Xinwen
X
Michael E DeBakey, Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mu
Hong
H
Chai
Hong
H
Liao
Dan
D
Yao
Qizhi
Q
Chen
Changyi
C
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000838:Anions / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000166:cytology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000838:Anions; D051242:Caveolin 1; D017320:HIV Protease Inhibitors; D009097:Multienzyme Complexes; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D013481:Superoxides; D000255:Adenosine Triphosphate; D002784:Cholesterol; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D048052:Mitogen-Activated Protein Kinase 3; D019438:Ritonavir