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

点击翻译按钮获取中文摘要

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.