title: Overexpression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD) provides protection against AZT- or 3TC-induced endothelial dysfunction.
abstract: 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.
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Glover
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: Valeria Y
authors.initials: VY
authors.lastname: Hebert
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: Krystle
authors.initials: K
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: Taylor M
authors.initials: TM
authors.lastname: Thibeaux
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Zavecz
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, LA 71130, United States. Electronic address: tammydugas@lsu.edu.
authors.forename: Tammy R
authors.initials: TR
authors.lastname: Dugas
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D019380:Anti-HIV Agents; D000975:Antioxidants; D019259:Lamivudine; D015215:Zidovudine; D013482:Superoxide Dismutase
keywords: Antioxidants; Atherosclerosis; Endothelial dysfunction; NRTI