162 - Combination Antiretroviral Therapy (cART) Altered Redox/Nitrosative genes, Enhanced Systemic Stress and Cardiac dysfunction in HIV-1 Transgenic (HIV-Tg) Rats: Effects of Magnesium Supplementation (Mg-Supp)

Abstract

We determined if clinically used cART promoted redox/nitrosative stress and cardiac toxicity in control and HIV-Tg rats and the effects of Mg. Treatment with cART (Truvada+atazanavir/ritonavir) up to 18 weeks, induced significant hypomagnesemia (-25%), elevated plasma 8-isoprostane, and RBC GSSG 2-3 folds (at 6 wks); plasma 3-nitrotyrosine (NT) increased 3.5-fold in the HIV-Tg rats (at 18 wks). In association, liver Nrf2 mRNA (by real time RT-PCR) was down-regulated 75% along with altered expression of HmOX-1 and GST; however iNOS and TNFα mRNAs were increased 2- & 4-fold. Prominent ventricular NT staining was observed in HIV-Tg+cART rats; echocardiography detected time-dependent moderate, but significant decreases in cardiac systolic (Fractional Shortening. -17%, 18 wks) and diastolic (E/A, -26%) functions. Mg-Supp (6X normal) in diet, substantially prevented rises in levels of 8-isoprostane, GSSG, and plasma NT. Most strikingly, Mg-Supp restored expressions of Nrf2 and HmOX-1, GST close to controls in HIV-Tg rats; both iNOS and TNFα up-regulations were blunted. In association, cardiac NT staining was substantially reduced; both cardiac systolic and diastolic functional decreases were attenuated 60-70% by Mg-supp. Conclusions cART treatment synergized with HIV-1 expression in down-regulating Nrf2 pathway, but up-regulating iNOS and TNFα expression; elevation of systemic redox/nitrosative stress contributed to cardiac dysfunction. The cardiac protective effects of Mg-Supp might be mediated by its antioxidant actions at the genomic and systemic levels through the Nrf2 pathway