RESUMEN
Nucleoside reverse transcriptase inhibitors (NRTIs) are considered the backbone of current combination therapies for HIV. These therapies have significantly decreased mortality and morbidity in HIV-infected patients, but some are associated with cardiovascular complications, including endothelial dysfunction, an early marker for atherosclerosis. Our prior studies demonstrated that co-treatment of cells with an antioxidant therapy reversed NRTI-induced endothelial injury. Thus, as a proof of concept that mitochondrially-targeted antioxidants may be useful in preventing NRTI toxicity, in the current study, mice overexpressing a mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), were compared with wild-type (WT) mice. Mice were treated chronically with either zidovudine (AZT), lamivudine (3TC), or tenofovir (TDF) to determine whether overexpression of MnSOD protected them from endothelial dysfunction. Endothelial function was assessed using vessel reactivity experiments on thoracic aortas as well as measures of endothelium derived factors nitric oxide (NO), endothelin-1 (ET-1), and prostacyclin. Oxidative stress was evaluated as levels of plasma 8-isoprostane. Alterations in vessel reactivity, NO, and ET-1 in WT mice treated with AZT or 3TC were noted. Overexpression of MnSOD offered protection from decreases in vessel reactivity and increases in ET-1. These findings indicate that mitochondrial oxidative stress induced by AZT or 3TC plays a major role in mediating NRTI-induced endothelial dysfunction, and suggest that the use of targeted antioxidants administered in conjunction with NRTIs may attenuate these effects.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Antioxidantes/metabolismo , Aorta Torácica/fisiopatología , Infecciones por VIH/enzimología , Lamivudine/efectos adversos , Mitocondrias/enzimología , Superóxido Dismutasa/metabolismo , Zidovudina/efectos adversos , Animales , Fármacos Anti-VIH/administración & dosificación , Aorta Torácica/efectos de los fármacos , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Humanos , Lamivudine/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Superóxido Dismutasa/genética , Zidovudina/administración & dosificaciónRESUMEN
BACKGROUND: Mitochondrial uncoupling protein 2 (UCP2) uncouples electron transport from ATP production. UCP2 has been shown to play an important role in obesity and diabetes. Interestingly, studies have demonstrated that UCP2 is up-regulated in human colon cancer samples. OBJECTIVE: In order to study the role of UCP2 in human cancers, we detected the UCP2 protein level in various human tumor tissues. METHODS: Six types of human tumor and adjacent normal tissue samples were collected and analyzed by Western blot assays to detect the levels of UCP2. RESULTS: The results showed that in the human head and neck, skin, prostate, and pancreatic tumor samples examined, the protein levels of UCP2 were significantly higher in tumor tissues than that in the adjacent normal tissues. The protein levels of UCP2 was lower in non-small cell lung tumor tissues, which is marginal significant. CONCLUSIONS: Over expression of UCP2 in certain tumors provides the rationale to speculate that UCP2 may promote tumor growth in these cancers.