HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages
James Dressman, … , Melinda E. Wilson, Eric J. Smart
James Dressman, … , Melinda E. Wilson, Eric J. Smart
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):389-397. https://doi.org/10.1172/JCI16261.
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Article AIDS/HIV

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-γ and CD36 mRNA levels in a PKC- and PPAR-γ–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

James Dressman, Jeanie Kincer, Sergey V. Matveev, Ling Guo, Richard N. Greenberg, Theresa Guerin, David Meade, Xiang-An Li, Weifei Zhu, Annette Uittenbogaard, Melinda E. Wilson, Eric J. Smart

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HIV protease inhibitors induce the accumulation of cholesteryl ester in ...
HIV protease inhibitors induce the accumulation of cholesteryl ester in THP-1 macrophages and human PBMCs. The human monocyte/macrophage cell line, THP-1, was cultured in 100 nM PMA for 72 hours to promote attachment and differentiation of the cells to a macrophage phenotype. In addition, we used freshly isolated and cultured human PBMCs (37) in these studies. The cells were incubated in the presence of 10% serum and 50 μg/ml of aggregated LDL along with 30 ng/ml of amprenavir, indinavir, ritonavir, or vehicle (ethanol) for 24 hours. The cells were lysed, lipids extracted, and processed to quantify total cellular cholesterol (a) or total cellular cholesteryl ester (b) by gas chromatography. Bars represent mean ± SE, n = 4 with triplicate measurements. *P < 0.01 compared with vehicle, #P < 0.01 compared with amprenavir, +P < 0.01 compared with indinavir. (c) THP-1 cells were lysed and 20 μg of protein was resolved by SDS-PAGE and immunoblotted with antibodies for CD36, SRA, and actin. Cross-reactive material was visualized by chemiluminescence. The exposure time was 2 minutes. The data are representative of five independent experiments. Essentially identical immunoblots were generated with human PBMCs (data not shown).