Protective Effects of Mg-Supplementation against Ritonavir-mediated Endothelial Oxidative Stress and lipid Metabolic Disorder
Open AccessThe object of this study was to determine if high Magnesium supplement could prevent ritonavir (RTV)-induced oxidative stress in bovine aortic endothelial cells (BAECs), and attenuate lipid metabolic disorders in Lewis-Brown Norway (LBN) F1 rats. In BAECs, cell viability, determined by the MTT assay, was reduced dose-dependently by 5, 10, 15, and 20uM of RTV; high Mg (2mM MgSO4) improved cell viability 11.43%, 12.04%, 18.56% (p < 0.01) and 10.32% (p < 0.05) respectively. Dihydroethidium (DHE) was used as indicator of BAEC superoxide anion. Under fluorescent imaging, 2mM MgSO4 substantially attenuated RTV-induced oxidized DHE signal. Flow cytometry was applied for relative quantification, showing that 2mM MgSO4 reduced superoxide level back to 108.28% of control, compared with RTV-alone (140.94%). 2,3-Diaminonaphthalene (DAN) fluorescence assay was used to detect nitrite level in the cell media. Treatment with 15uM RTV decreased nitrite levels to 84% (24hr) and 62% (48hr) of control, which were returned to 100.65% (p < 0.01) and 79% (p < 0.05), respectively, by high Mg-cotreatment. Concomitantly, the BAEC eNOS mRNA level was significantly diminished to 75% by RTV (15uM) and was upregulated to 107% (p < 0.01) by 2mM MgSO4. High Mg-supplement's effect in preserving eNOS mRNA level was further observed in livers of RTV-treated (5 weeks) LBN rat; changes in plasma nitrite levels also showed a trend similar to that in the BAEC media. Additionally, we found high Mg-diet completely reversed downregulation of cyp7a1, cited2 and g6pc, and upregulation of me1; all 4 genes are related to lipid metabolism. In conclusion, these results suggest that high magnesium supplementation may provide beneficial effects against RTV-induced toxicity due to its endothelial antioxidant property and potential inhibition against drug induced hyperlipidemia.
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