HIV Protease Inhibitors, the Unfolded Protein Response and Atherosclerosis

描述（由申请人提供）：HIV蛋白酶抑制剂已成功用于HIV感染的高效抗逆转录病毒治疗（HAART）。在HAART治疗中掺入蛋白酶抑制剂可对病毒复制产生深远和持续的抑制，显著降低发病率和死亡率，延长HIV感染患者的寿命。不幸的是，HIV蛋白酶抑制剂的益处被一些代谢异常所损害。HIV蛋白酶抑制剂治疗最有害的副作用之一是血脂异常的发展，这是动脉粥样硬化发展的一个公认的危险因素。然而，HIV蛋白酶抑制剂促进动脉粥样硬化的确切机制尚不清楚。巨噬细胞是参与动脉粥样硬化病变的最重要的细胞类型，在动脉粥样硬化的各个阶段都起着关键作用。部分巨噬细胞发生凋亡，特别是在晚期病变中，这是由多种因素调节或控制的。诱导巨噬细胞凋亡的一个关键步骤是破坏内质网（ER）稳态，从而触发内质网应激信号转导通路，即未折叠蛋白反应（UPR）。UPR在调节细胞生长、分化和凋亡中起关键作用。重要的是，UPR与动脉粥样硬化病变中的巨噬细胞凋亡有关。我们的初步数据表明，使用HIV蛋白酶抑制剂治疗会增加细胞内游离胆固醇的积累，激活UPR，并诱导巨噬细胞凋亡。基于这些新发现，我们假设HIV蛋白酶抑制剂通过破坏脂质稳态、激活UPR和诱导巨噬细胞凋亡来促进动脉粥样硬化。为了验证这一假设，提出了三个具体目标。目的1：确定临床使用的HIV蛋白酶抑制剂对培养巨噬细胞和体内UPR激活的影响。目的2：阐明巨噬细胞中HIV蛋白酶抑制剂激活UPR的细胞/分子机制。目的3：确定体内小鼠模型中HIV蛋白酶抑制剂诱导的UPR激活是否与动脉粥样硬化病变的形成有关。这些特定目标的完成将有助于确定和建立HIV蛋白酶抑制剂诱导动脉粥样硬化的新的细胞/分子机制，从而增强我们对haart相关心血管疾病机制的理解，并为开发新的治疗策略提供新的信息。

DESCRIPTION (provided by applicant): HIV protease inhibitors have been successfully used in highly active anti-retroviral therapy (HAART) for HIV infection. Incorporation of protease inhibitors in HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality, and prolongs the lifespan of patients with HIV infection. Unfortunately, the benefits of HIV protease inhibitors are compromised by a number of metabolic abnormalities. One of the most deleterious side effects of HIV protease inhibitor therapy is the development of dyslipidemia, which is a well established risk factor for the development of atherosclerosis. However, the exact mechanisms by which HIV protease inhibitors promote atherosclerosis remain unclear. Macrophages are the most prominent cell type involved in atherosclerotic lesions and play key roles in all phases of atherosclerosis. A portion of macrophages become apoptotic, particularly in advanced lesions, which is regulated or controlled by numerous factors. One critical step for inducing macrophage apoptosis is to disrupt endoplasmic reticulum (ER) homeostasis, thus triggering the ER stress signal transduction pathway, known as the unfolded protein response (UPR). UPR plays a critical role in regulating cell growth, differentiation, and apoptosis. Importantly, the UPR has been linked to macrophage apoptosis in atherosclerotic lesions. Our preliminarily data demonstrate that treatment with HIV protease inhibitors increases the accumulation of intracellular free cholesterol, activates the UPR, and induces apoptosis in macrophages. Based on these novel findings, we HYPOTHESIZE that HIV protease inhibitors promote atherosclerosis by disrupting lipid homeostasis, activating the UPR, and inducing apoptosis in macrophages. Three specific aims are proposed to test the hypothesis. Aim#1: To determine the effects of clinically used HIV protease inhibitors on UPR activation both in cultured macrophages and in vivo. Aim#2: To elucidate the cellular/molecular mechanisms leading to UPR activation by HIV protease inhibitors in macrophages. Aim#3: To determine whether HIV protease inhibitor-induced UPR activation is responsible for the formation of atherosclerotic lesions in vivo mouse models. Completion of these specific aims will help identify and establish new cellular/molecular mechanisms of HIV protease inhibitor-induced atherosclerosis, thereby enhancing our understanding of the mechanisms of HAART-associated cardiovascular diseases and providing novel information for the development of new therapeutic strategies.