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• W2293552644 abstract "The use of HIV protease inhibitors (PIs) has extended the duration and quality of life for HIV-positive individuals. However there is increasing concern that this antiviral therapy may promote premature cardiovascular disease by impairing endothelial cell (EC) function. In the present study, we investigated the effect of HIV PIs on EC function and determined if the enzyme heme oxygenase (HO-1) influences the biological action of these drugs. We found that three distinct PIs, including ritonavir, atazanavir, and lopinavir, stimulated the expression of HO-1 protein and mRNA. The induction of HO-1 was associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). PIs also stimulated HO-1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the PI-mediated induction of HO-1 was abolished by N-acetyl-l-cysteine and rotenone. Furthermore, PIs blocked EC proliferation and migration and stimulated the expression of intercellular adhesion molecule-1 and the adhesion of monocytes on ECs. Inhibition of HO-1 activity or expression potentiated the anti-proliferative and inflammatory actions of PIs which was reversed by bilirubin but not carbon monoxide. Alternatively, adenovirus-mediated overexpression of HO-1 attenuated the growth-inhibitory and inflammatory effect of PIs. In contrast, blocking HO-1 activity failed to modify the anti-migratory effect of the PIs. Thus, induction of HO-1 via the ROS–Nrf2 pathway in human ECs counteracts the anti-proliferative and inflammatory actions of PIs by generating bilirubin. Therapeutic approaches targeting HO-1 may provide a novel approach in preventing EC dysfunction and vascular disease in HIV-infected patients undergoing antiretroviral therapy." @default.
• W2293552644 created "2016-06-24" @default.
• W2293552644 creator A5000979448 @default.
• W2293552644 creator A5006163152 @default.
• W2293552644 creator A5070064210 @default.
• W2293552644 creator A5071459890 @default.
• W2293552644 date "2016-05-01" @default.
• W2293552644 modified "2023-09-26" @default.
• W2293552644 title "Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction" @default.
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• W2293552644 doi "https://doi.org/10.1016/j.freeradbiomed.2016.03.003" @default.
• W2293552644 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4844824" @default.
• W2293552644 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26968795" @default.
• W2293552644 hasPublicationYear "2016" @default.
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