HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages
HIV protease inhibitors promote atherosclerotic lesion formation independent of dyslipidemia by increasing CD36-dependent cholesteryl ester accumulation in macrophages
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DOI：
10.1172/jci200316261
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发表时间：
2003-02-01
影响因子：
15.9
通讯作者：
Smart, EJ
中科院分区：
文献类型：
--
作者：
Dressman, J;Kincer, J;Smart, EJ
蛋白酶抑制剂可降低HIV患者的病毒载量，但患者仍会出现高甘油三酯血症、高胆固醇血症和动脉粥样硬化。人们一直认为，动脉粥样硬化中蛋白酶抑制剂依赖性的增加是继发于血脂异常的。用蛋白酶抑制剂孵育THP-1细胞或人pbmc可引起CD36的上调和胆固醇的积累。酯类。使用CD36阻断抗体、CD36 morpholino和从CD36缺失小鼠中分离的单核细胞表明，蛋白酶抑制剂诱导的胆固醇酯的增加依赖于CD36的上调。这些数据导致了一种假设，即蛋白酶抑制剂通过上调CD36和胆固醇酯积累而独立于血脂异常，从而诱导泡沫细胞形成并导致动脉粥样硬化。对低密度脂蛋白受体缺失小鼠的研究表明，低剂量的蛋白酶抑制剂诱导腹腔巨噬细胞中CD36和胆固醇酯水平的增加和动脉粥样硬化的发展，而不改变血浆脂质。此外，缺乏CD36保护动物免受蛋白酶抑制剂诱导的动脉粥样硬化。最后，利托那韦以PKC和ppar - γ依赖的方式增加ppar - γ和CD36 mRNA水平。我们得出结论，蛋白酶抑制剂通过促进巨噬细胞中CD36的上调和随后的固醇积累，促进动脉粥样硬化的形成。
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.