Protective Efficacy of Mg-Supplementation Against NRTI-induced Cardiac Toxicity

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DESCRIPTION (provided by applicant): Zidovudine (AZT) cardiotoxicity in HIV patients has been well documented, but the potential beneficial effect of magnesium (Mg)-supplementation has never be explored. AZT toxicity is linked to increased oxidative stress which may be mediated by abnormal iron status. Since other clinically used nucleoside reverse transcriptase inhibitor (NRTI) drugs are structurally similar to AZT, their potential interaction with endogenous iron may represent a common mechanism of oxidative toxicity. Our in vitro studies suggest that AZT synergizes with iron in causing endothelial cytotoxicity and that supra levels of extracellular magnesium are cytoprotective. This proposal will explore whether dietary supplementation of either Mg oxide (inorganic) or Mg gluconate (an organic salt) will attenuate chronic NRTI-induced systemic inflammation and cardiac injury n vivo, and if the protective mechanism(s) associated with the Mg supplements can be revealed using NRTI- treated in vitro models. The specific aims are: (1) Determine the differential protective effects of upplemental inorganic and organic Mg-salts against AZT (and other NRTIs)-mediated membrane and endothelial cell oxidative injury; (2) Assess if dietary supplementation of Mg-salts (Mg oxide and Mg- gluconate: 3 and 6- fold higher than normal) in the rat attenuates chronic AZT-induced cardiovascular inflammation, oxidative stress, and neutrophil activation; and (3) Determine if Mg-supplementation attenuates AZT-enhanced myocardial susceptibility to imposed ischemia/reperfusion (I/R) stress ex vivo. We will employ immunohistochemical and pathology techniques to localize inflammatory cyokines and white blood cell infiltrates. Oxidative stress in vivo will be determined biochemically by changes in tissue/blood glutathione status, iron status, and lipid peroxidation products (F2-isoprostanes, conjugated dienes). Changes in tolerance to perfused heart l/R-stress will be determined by free radical production (ESR spin trapping), and alterations in oxidative tissue injury markers and functional recovery. This proposed exploratory effort may reveal a potential usefulness of Mg-supplements as an effective, yet relatively inexpensive adjunct therapy to lessen NRTI-related cardiovascular toxicity.