HIV Protease Inhibitors and Atherosclerosis

描述：(申请人提供)我们假设HIV蛋白水解酶 抑制剂改变巨噬细胞B类清道夫受体依赖的摄取和 胆固醇的外流从而促进脂质的形成 巨噬细胞和动脉粥样硬化病变。使用艾滋病毒的一个主要缺点 蛋白水解酶抑制剂的作用是促进血脂异常的发展， 是动脉粥样硬化发展的既定危险因素。数不胜数 已有报告表明，蛋白水解酶抑制剂治疗和 动脉粥样硬化；然而，这并没有明确地在 大规模临床试验。血脂异常，这主要是由于 甘油三酯，不太可能完全解释 HIV患者的动脉粥样硬化病变，因为动脉粥样硬化是一种 不受单一因素控制的多因素疾病。我们的 初步数据表明，艾滋病毒蛋白水解酶抑制剂具有直接作用 巨噬细胞是动脉粥样硬化病变中的关键细胞介质 发展。富含脂质的巨噬细胞的产生是 动脉粥样硬化的形成，并被认为部分是由于不受控制的摄取 修饰的脂蛋白。这种异常的胆固醇积聚受 B类清道夫受体SR-BI和CD36的功能。两者都有 受体存在于动脉粥样硬化病变和巨噬细胞上。此外, 两种受体均可介导脂蛋白胆固醇的摄取和外排。 细胞胆固醇的含量。我们的初步数据显示腹膜 给予HIV蛋白酶的低密度脂蛋白受体缺陷小鼠巨噬细胞的分离 氨丙那韦、吲哚那韦或利托那韦等抑制剂含有更多的SR-BI和CD36 而不是年龄匹配的对照组。此外，三种蛋白水解酶抑制剂 巨噬细胞模型THP-1细胞SR-BI和CD36水平升高 系统。蛋白水解酶抑制剂也增加了细胞中的胆固醇含量。 在体内和体外模型系统中，这与我们的 假设。重要的是，服用氨丙那韦、吲哚那韦或利托那韦的小鼠有 显著多于对照组小鼠的动脉粥样硬化病变。我们将测试两个 明确的目标。目的1：研究HTV蛋白水解酶抑制剂对HTV蛋白表达的影响。 SR-BI和CD36依赖于胆固醇的摄取和外流。目标2：确定 白细胞(即巨噬细胞等)HIV蛋白水解酶抑制剂的特异性作用 低密度脂蛋白受体缺失小鼠动脉粥样硬化病变形成的研究 用SR-BI x LDLR和CD36 x LDLR缺失小鼠的骨髓移植。

DESCRIPTION: (provided by applicant) We hypothesize that HIV protease inhibitors alter macrophage class B scavenger receptor-dependent uptake and efflux of cholesterol thereby promoting the formation of lipid-laden macrophages and atherosclerotic lesions. A major drawback to the use of HIV protease inhibitors is that they promote the development of dyslipidemia, which is an established risk factor for the development of atherosclerosis. Numerous reports have suggested a causal link between protease inhibitor therapy and atherosclerosis; however, this has not been unequivocally demonstrated in a large-scale clinical trial. The dyslipidemia, which is primarily an increase in triglycerides, is unlikely to completely account for the development of atherosclerotic lesions in HIV patients because atherosclerosis is a multifactorial disease that is not controlled by a single factor. Our preliminary data demonstrate that HIV protease inhibitors have direct effects on macrophages, which are critical cellular mediators in atherosclerotic lesion development. The generation of lipid-laden macrophages is a key event in atherogenesis and is thought to be due, in part, to unregulated uptake of modified lipoproteins. Such aberrant cholesterol accumulation is influenced by the functions of the class B scavenger receptors, SR-BI and CD36. Both receptors are found in atherosclerotic lesions and on macrophages. In addition, both receptors can mediate the uptake of lipoprotein cholesterol and the efflux of cellular cholesterol. Our preliminary data demonstrate that peritoneal macrophages isolated from LDL receptor null mice given the HIV protease inhibitors, amprenavir, indinavir, or ritonavir, contain more SR-BI and CD36 than aged-matched controls. In addition, all three protease inhibitors increased SR-BI and CD36 levels in THP-1 cells, our macrophage cell model system. The protease inhibitors also increased the cellular cholesterol content in both the in vivo and in vitro model systems, which is consistent with our hypothesis. Importantly, mice given amprenavir, indinavir, or ritonavir had significantly more atherosclerotic lesions than control mice. We will test two Specific Aims. Aim 1 : To determine the effects of HTV protease inhibitors on SR-BI and CD36 dependent cholesterol uptake and efflux. Aim 2: To determine the leukocyte (i.e., macrophages, etc.) specific effects of HIV protease inhibitors on atherosclerotic lesion formation in LDL receptor null mice that have been transplanted with bone marrow from SR-BI x LDLR and CD36 x LDLR null mice.