| Title | HIV-1 antiretrovirals induce oxidant injury and increase intima-media thickness in an atherogenic mouse model. | | Author(s) | Jiang B, Hebert VY, Khandelwal AR, Stokes KY, Dugas TR | | Institution | Departments of Pharmacology, Toxicology and Neuroscience and Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, United States. | | Source | Toxicol Lett 2009 Jun 22; 187(3):164-71. | | Abstract | A growing body of evidence suggests HIV patients are at a greater risk for developing atherosclerosis. However, clinical investigations have generated conflicting results with regard to whether antiretrovirals are independently involved in the development of HIV-associated atherosclerosis. By administering antiretrovirals in an atherogenic mouse model, we determined whether two commonly prescribed antiretrovirals, the protease inhibitor indinavir and the nucleoside reverse transcriptase inhibitor AZT, can induce premature atherosclerosis. C57BL/6 mice were administered an atherogenic diet+/-AZT, indinavir, or AZT plus indinavir for 20 weeks. Aortic intima-media thickness (IMT) and cross-sectional area (CSA) were determined. Compared to controls, treatment with AZT, indinavir or AZT plus indinavir, significantly increased aortic IMT and CSA. This suggests that antiretrovirals can directly exacerbate atherogenesis, in the absence of interaction with a retroviral infection. To elucidate the role of oxidant injury in the drug-induced initiation of atherosclerosis, a separate group of mice were treated for 2 weeks with an atherogenic diet+/-AZT, indinavir or AZT plus indinavir. Aortic reactive oxygen species (ROS) production and glutathione/glutathione disulfide (GSH/GSSG) ratios, as well as plasma levels of 8-isoprostanes (8-iso-PGF(2alpha)) and lipids were determined. At 2 weeks, aortic ROS was increased and GSH/GSSG ratios were decreased in all antiretroviral treatment groups. Plasma 8-iso-PGF(2alpha) was increased in the AZT and AZT plus indinavir-treated groups. At 20 weeks, increased ROS production was maintained for the AZT and indinavir treatment groups, and increased 8-iso-PGF(2alpha) levels remained elevated in the AZT treatment group. Cholesterol levels were moderately elevated in the AZT and AZT plus indinavir-treated groups at 2 but not 20 weeks. Conversely, indinavir treatment increased plasma cholesterol at 20 but not 2 weeks. Thus, though effects on plasma lipid levels occurred, with effects of the individual antiretrovirals variable across the treatment period, there was consistent evidence of oxidant injury across both early and late time points. Together with the known metabolic abnormalities induced by antiretrovirals, drug-induced oxidant production may contribute to the development of antiretroviral-associated atherosclerosis. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19429260 |
|
