Cardiotoxicity seen in HIV patients receiving long-term treatment with zidovudine (AZT) may occur against a background of multiple risk factors: abnormal tissue iron status, nutritional Mg-deficiency (MgD), inflammation and oxidative stress. This proposal will evaluate if chronic AZT treatment synergizes with co-existing MgD to enhance iron imbalance, and resultant oxidative stress in vivo. Recent data from our lab also suggest that AZT-mediated gut injury may promote subsequent endotoxic injury to cardiac and hepatic tissue. This led us to propose the following Specific Aims: (1) Determine if AZT causes systemic oxidative stress, tissue inflammation, and altered tissue iron status in chronically-treated rats and in inflammatory cell models. (2) Assess whether chelation or antibiotic therapy attenuates endotoxemia, indices of tissue and cell oxidative stress, and tissue inflammation in chronic AZT-treated animals. (3) Evaluate if AZT treatment synergizes with MgD to enhance tissue injury in vivo due to increased iron disturbances; and assess the protective efficacy of chelation and antibiotic therapy. (4) Determine if AZT treatment synergizes with MgD to enhance myocardial susceptibility to imposed I/R stress ex vivo; and assess the protective efficacy of in vivo chelation therapy. Sensitive immunocytochemical and molecular biology techniques will be used to localize and quantify cytokines, adhesion molecules, and apoptosis in the myocardium. Oxidative stress will be determined by measuring tissue glutathione and protein-thiol status, lipid peroxidation products, nitric oxide and peroxynitrite marker, as well as free radical production (ESR spin-trapping) and dysfunction in isolated ischemia/reperfused hearts. The main goal is to assess whether AZT, in conjunction with MgD, will further alter iron status, leading to enhanced sensitivity of cardiac, hepatic and intestinal tissue to oxidative stress. The proposed iron chelation and antibiotic intervention strategies may lead to adjunct therapies aimed at lessen AZT-related cardiovascular toxicity. ? ?
| Weglicki, William B; Mak, Iu Tong; Chmielinska, Joanna J et al. (2010) The role of magnesium deficiency in cardiovascular and intestinal inflammation. Magnes Res 23:S199-206 |
| Weber, Karl T; Weglicki, William B; Simpson, Robert U (2009) Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res 81:500-8 |
| Mak, I Tong; Chmielinska, Joanna J; Kramer, Jay H et al. (2009) AZT-induced oxidative cardiovascular toxicity: attenuation by Mg-supplementation. Cardiovasc Toxicol 9:78-85 |
| Kramer, Jay H; Spurney, Christopher; Iantorno, Micaela et al. (2009) Neurogenic inflammation and cardiac dysfunction due to hypomagnesemia. Am J Med Sci 338:22-7 |
| Weglicki, William B; Chmielinska, Joanna J; Tejero-Taldo, Isabel et al. (2009) Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia. Magnes Res 22:167S-173S |
| Mak, I T; Kramer, J H; Chmielinska, J J et al. (2008) Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat. Inflamm Res 57:300-5 |
| Tejero-Taldo, M Isabel; Chmielinska, Joanna J; Weglicki, William B (2007) Chronic dietary Mg2+ deficiency induces cardiac apoptosis in the rat heart. Magnes Res 20:208-12 |
| Komarov, Andrei M; Hall, Jonathon M; Chmielinska, Joanna J et al. (2006) Iron uptake and release by macrophages is sensitive to propranolol. Mol Cell Biochem 288:213-7 |
| Tejero-Taldo, Maria Isabel; Kramer, Jay Harlan; Mak, Iu Tong et al. (2006) The nerve-heart connection in the pro-oxidant response to Mg-deficiency. Heart Fail Rev 11:35-44 |
| Komarov, Andrei M; Hall, Jonathon M; Weglicki, William B (2004) Azidothymidine promotes free radical generation by activated macrophages and hydrogen peroxide-iron-mediated oxidation in a cell-free system. Biochim Biophys Acta 1688:257-64 |
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