HAART-mediated Cardiovascular Toxcity in HIV-1 Transgenic Rats: Mg Protection

摘要：利托那韦增效阿扎那韦(ATV/RTV) +特鲁瓦达[富马酸替诺福韦二氧吡酯/恩曲他滨（TDF/FTC）]联合治疗目前被推荐为抗逆转录病毒初始患者的一线HAART治疗之一。这种治疗方案虽然能有效抑制HIV-1复制，但在HIV-1患者中长期使用可能会导致高脂血症/内皮氧化应激、肾毒性和心脏损伤。我们最近证明单独AZT或单独RTV可引起大鼠心脏炎症和功能障碍增强；RTV进一步引起高脂血症和eNOS下调。重要的是，我们已经证明，单独补充膳食镁可以减少大部分AZT或rtv副作用。由于HIV-1蛋白表达可能分别导致显著的全身和心血管炎症，我们假设在HIV-1感染期间，haart介导的慢性心血管副作用进一步增强，补充mg可能具有保护作用。为了验证这些假设，我们建议使用已建立的HIV-1转基因大鼠模型和父母Fischer 344大鼠进行以下具体目的：1)与对照大鼠相比，确定HAART联合治疗是否进一步促进了HIV-1转基因大鼠的全身氧化/亚氧化应激、高脂血症和心脏病理和功能障碍。2)确定补充镁是否能减轻HIV-1 Tg和对照大鼠haart介导的全身炎症、病理和心功能障碍。采用生化和免疫组织化学技术定量测定氧化/亚硝化、脂质代谢和病理指标；HAART/HIV-1诱导eNOS下调和Mg效应将通过qRT-PCR、western blot和NO代谢物进行评估。心功能将通过超声心动图原位测定。预计的结果可能会对选择补充镁作为一种有效和安全的联合疗法来对抗目前大多数HAART治疗方案引起的HIV患者慢性心血管毒性产生重大影响。

DESCRIPTION (provided by applicant): Abstract: Ritonavir-boosted atazanavir (ATV/RTV) + Truvada [tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)] combination is currently recommended as one of the first line HAART therapy for the antiretroviral-naive patients. This regimen, while being effective to suppress HIV-1 replication, may prove to have hyperlipidemia/endothelial oxidative stress, renal toxicity and injurious cardiac effects when chronically used in HIV-1 patients. We recently demonstrate that AZT alone or RTV alone can cause enhanced cardiac inflammation and dysfunction in rats; RTV further caused hyperlipidemia and eNOS down-regulation. Importantly, we have demonstrated that dietary Mg-supplementation alone diminished most of the AZT- or RTV-side effects. Since HIV-1 protein expression may separately lead to significant systemic and cardiovascular inflammation, we hypothesize that HAART-mediated chronic cardiovascular side effects are enhanced further during HIV-1 infection, and Mg-supplementation may be protective. To pursue these hypotheses, we propose to use an established HIV-1 transgenic rat model and the parent Fischer 344 rats for the following specific Aims: 1) Determine if HAART combination treatment further promotes systemic oxidative/nitrosative stress, hyperlipidemia and cardiac pathology and dysfunction in HIV-1 Transgenic Rats compared with HAART treatment in control rats. 2) Determine if Mg-supplementation attenuates HAART-mediated systemic inflammation, pathology, and cardiac dysfunction in HIV-1 Tg and control rats. Oxidative/nitrosative, lipid metabolic and pathological indices will be quantified by biochemical and immunohistochemical techniques; HAART/HIV-1 induced eNOS down-regulation and Mg effects will be assessed by qRT-PCR and western blot and by NO metabolites. Cardiac function will be determined in situ by echocardiography. The projected results may have a major impact on choosing Mg- supplementation as an effective and safe co-therapy against chronic cardiovascular toxicity induced by most current HAART regimens in HIV patients.