title: HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages.
abstract: Protease inhibitors decrease the viral load in HIV patients, however the patients develop hypertriglyceridemia, hypercholesterolemia, and atherosclerosis. It has been assumed that protease inhibitor-dependent increases in atherosclerosis are secondary to the dyslipidemia. Incubation of THP-1 cells or human PBMCs with protease inhibitors caused upregulation of CD36 and the accumulation of cholesteryl esters. The use of CD36-blocking antibodies, a CD36 morpholino, and monocytes isolated from CD36 null mice demonstrated that protease inhibitor-induced increases in cholesteryl esters were dependent on CD36 upregulation. These data led to the hypothesis that protease inhibitors induce foam cell formation and consequently atherosclerosis by upregulating CD36 and cholesteryl ester accumulation independent of dyslipidemia. Studies with LDL receptor null mice demonstrated that low doses of protease inhibitors induce an increase in the level of CD36 and cholesteryl ester in peritoneal macrophages and the development of atherosclerosis without altering plasma lipids. Furthermore, the lack of CD36 protected the animals from protease inhibitor-induced atherosclerosis. Finally, ritonavir increased PPAR-gamma and CD36 mRNA levels in a PKC- and PPAR-gamma-dependent manner. We conclude that protease inhibitors contribute to the formation of atherosclerosis by promoting the upregulation of CD36 and the subsequent accumulation of sterol in macrophages.
authors.affiliation: Department of Physiology, University of Kentucky Medical School, Lexington, Kentucky 40536, USA.
authors.forename: James
authors.initials: J
authors.lastname: Dressman
authors.forename: Jeanie
authors.initials: J
authors.lastname: Kincer
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Matveev
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Richard N
authors.initials: RN
authors.lastname: Greenberg
authors.forename: Theresa
authors.initials: T
authors.lastname: Guerin
authors.forename: David
authors.initials: D
authors.lastname: Meade
authors.forename: Xiang-An
authors.initials: XA
authors.lastname: Li
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.forename: Annette
authors.initials: A
authors.lastname: Uittenbogaard
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Wilson
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Smart
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced*; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006949:Hyperlipidemias / Q000188:drug therapy; D007075:Immunoglobulin M / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D002788:Cholesterol Esters; D017320:HIV Protease Inhibitors; D007075:Immunoglobulin M; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D011493:Protein Kinase C