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

描述（由申请人提供）：摘要：利托那韦增强的阿扎那韦（ATV/RTV）+ Truvada [富马酸替诺福韦酯/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治疗之一。该方案虽然有效抑制HIV-1复制，但当长期用于HIV-1患者时，可能证明具有高脂血症/内皮氧化应激、肾毒性和损伤心脏效应。我们最近证明，AZT单独或RTV单独可以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，膳食镁补充剂单独减少了大多数AZT或RTV的副作用。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HAART介导的慢性心血管副作用在HIV-1感染期间进一步增强，镁补充剂可能具有保护作用。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大鼠用于以下特定目的：1）确定与对照大鼠中的HAART治疗相比，HAART组合治疗是否进一步促进HIV-1转基因大鼠中的全身性氧化/亚硝化应激、高脂血症和心脏病理和功能障碍。2)确定镁补充是否减弱HAART介导的全身炎症，病理学和心功能不全的HIV-1 Tg和对照大鼠。将通过生物化学和免疫组织化学技术定量氧化/亚硝化、脂质代谢和病理学指标;将通过qRT-PCR和蛋白质印迹以及NO代谢物评估HAART/HIV-1诱导的eNOS下调和Mg效应。将通过超声心动图原位测定心脏功能。预测的结果可能对选择镁补充剂作为有效和安全的联合疗法对抗HIV患者中大多数当前HAART方案诱导的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.