Prevent HIV protease inhibitor-induced atherosclerosis by Berberine

描述(由申请人提供)：人类免疫缺陷病毒(HIV)蛋白酶抑制剂(PI)已成功地用于HIV感染的高效抗逆转录病毒疗法(HAART)。在HAART中引入HIV Pis可显著抑制病毒复制，显著降低发病率和死亡率，并延长HIV感染患者的生命。然而，超过50%的接受HAART的患者会出现血脂异常和糖尿病，这些都是众所周知的严重心血管并发症的危险因素，包括内皮功能障碍和动脉粥样硬化。虽然HIV PI诱导动脉粥样硬化的机制尚未完全确定，但越来越多的证据表明，可能涉及多种机制，不同的PI对脂代谢可能有不同的影响。开发其他治疗干预措施来对抗艾滋病毒PI相关的并发症尤为紧迫，这一发展是这一应用的长期目标。动脉粥样硬化是一种慢性炎症性疾病，巨噬细胞在动脉粥样硬化病变的发生和发展中起着关键作用。炎症和细胞凋亡是动脉粥样硬化病理生理过程中的两个重要事件。我们最近证实，HIV Pis激活未折叠蛋白反应(UPR)，诱导细胞凋亡，并促进巨噬细胞泡沫细胞的形成。黄连素(berberine，BBR)是一种从多种中草药中分离得到的异喹啉生物碱，具有显著的抗炎活性，近年来被鉴定为一种新型的降胆固醇药物。我们的初步研究还表明，BBR强烈地抑制了HIV PI诱导的UPR激活、泡沫细胞的形成以及巨噬细胞中TNF-α和IL-6的释放。基于这些观察，我们推测BBR能够通过抑制巨噬细胞中UPR的激活和炎症反应来预防HIV PI诱导的动脉粥样硬化。为了检验这一假说，本文提出了三个具体目标。目的1：阐明BBR抑制HIV PI诱导的巨噬细胞UPR活化的细胞/分子机制。目的#2：探讨BBR抑制HIV-PI诱导巨噬细胞产生肿瘤坏死因子-α和白介素6的细胞/分子机制。目的#3：在活体动物模型上，确定补肾活血方能否预防HIV-Pis所致的血脂异常和动脉粥样硬化。越来越多的人注意使用补充和替代医学(CAM)作为艾滋病毒感染和HAART相关并发症治疗的一部分。了解BBR预防HIV PI诱导的血脂异常和动脉粥样硬化的机制具有重要的临床意义。完成这些具体目标将有助于确定和建立新的艾滋病毒感染治疗战略。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) protease inhibitors (Pis) have been used successfully in highly active anti-retroviral therapy (HAART) for HIV infection. Incorporation of HIV Pis 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. However, more than 50% of patients receiving HAART develop lipid abnormalities and diabetes, which are well-known risk factors for serious cardiovascular complications including endothelial dysfunction and atherosclerosis. Although the mechanism underlying HIV Pi-induced atherosclerosis remains to be fully identified, an increasing body of evidence suggests that multiple mechanisms may be involved, and individual Pis may have different effects on lipid metabolism. The development of other therapeutic interventions to counteract the HIV Pi-associated complications are especially urgent, and this development is the long-term objective of this application. Atherosclerosis is a chronic inflammatory disease and macrophages play a critical role in the initiation and progression of atherosclerotic lesions. Both inflammation and apoptosis are two major events in the pathophysiology of atherosclerosis. We have recently demonstrated that HIV Pis activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. Berberine (BBR), an isoquinoline alkaloid isolated from many medicinal herbs, has significant anti-inflammatory activity and recently has been identified as a novel cholesterol-lowering drug. Our preliminary studies also indicate that BBR strongly inhibits HIV Pi-induced UPR activation, foam cell formation, and TNF-a and IL-6 release in macrophages. Based on these observations, we HYPOTHESIZE that BBR is able to prevent HIV Pi-induced atherosclerosis by inhibiting the UPR activation and the inflammatory response in macrophages. Three specific aims are proposed to test the hypothesis. Aim#1: To elucidate the cellular/molecular mechanisms by which BBR inhibits HIV Pi-induced UPR activation in macrophages. Aim#2: To determine cellular/molecular mechanisms by which BBR inhibits HIV Pi-induced TNF-a and IL-6 synthesis in macrophages. Aim#3: To determine whether BBR is able to prevent the dyslipidemia and atherosclerosis induced by HIV Pis in an in vivo animal model. An increasing amount of attention has been paid to the use of complementary and alternative medicine (CAM) as a part of the treatment for HIV infection and the complications associated with HAART. Understanding the mechanisms by which BBR prevents HIV Pi- induced dyslipidemia and atherosclerosis is of great clinical importance. Completion of these specific aims will help identify and establish new therapeutic strategies for HIV infection.