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

描述(申请人提供)：摘要：利托那韦助剂阿扎那韦(ATV/RTV)特鲁瓦达[替诺福韦富马酸异丙酯/恩曲他滨(TDF/FTC)]组合目前被推荐为抗逆转录病毒初治患者的一线HAART疗法之一。这种方案虽然有效地抑制了HIV-1的复制，但当长期用于HIV-1患者时，可能会被证明具有高脂血症/内皮细胞氧化应激、肾脏毒性和损害心脏的影响。我们最近证明，单独使用AZT或单独使用RTV可导致大鼠心脏炎症和功能障碍的增加；RTV进一步导致高脂血症和eNOS下调。重要的是，我们已经证明，仅补充膳食镁就可以减少大多数AZT或RTV的副作用。由于HIV-1蛋白的表达可能分别导致显著的全身和心血管炎症，我们假设HAART介导的慢性心血管副作用在HIV-1感染期间进一步增强，补充镁可能具有保护作用。为了实现这些假设，我们建议使用已建立的HIV-1转基因大鼠模型和亲本Fischer 344大鼠来实现以下特定目的：1)确定与对照大鼠的HAART治疗相比，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/亚硝酸盐应激、高脂血症和心脏病理及功能障碍。2)确定补充镁是否能减轻HAART介导的全身炎症、病理和心功能不全。氧化/亚硝化、脂质代谢和病理指标将通过生化和免疫组织化学技术进行量化；HAART/HIV-1诱导的eNOS下调和镁的作用将通过qRT-PCR和蛋白质印迹以及NO代谢产物来评估。心功能将通过超声心动图进行原位检测。预计的结果可能会对选择镁补充剂作为一种有效和安全的联合治疗方案产生重大影响，以对抗目前大多数HAART方案对HIV患者造成的慢性心血管毒性。

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.