Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction.
Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction.
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DOI：
10.1016/j.freeradbiomed.2016.03.003
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发表时间：
2016-05
影响因子：
7.4
通讯作者：
Durante W
中科院分区：
文献类型：
--
作者：
Liu XM;Durante ZE;Peyton KJ;Durante W
HIV蛋白酶抑制剂（PI）的使用延长了HIV阳性个体的生存时间和生活质量。然而，越来越多的人担心这种抗病毒治疗可能会通过损害内皮细胞（EC）功能而促进过早的心血管疾病。在本研究中，我们研究了HIV PI对EC功能的影响，并确定了血红素加氧酶（HO-1）是否影响这些药物的生物学作用。我们发现，三种不同的PI，包括利托那韦，阿扎那韦，洛匹那韦，刺激HO-1蛋白和mRNA的表达。HO-1的诱导与NF-E2相关因子-2（Nrf 2）活性和活性氧（ROS）的增加有关。PI也刺激HO-1启动子活性，这是防止突变的抗氧化剂响应元件或过表达显性负Nrf 2。此外，PI介导的HO-1诱导被N-乙酰-L-半胱氨酸和鱼藤酮取消。PI还能抑制EC的增殖和迁移，促进细胞间粘附分子-1的表达和单核细胞对EC的粘附。抑制HO-1活性或表达增强PI的抗增殖和炎症作用，胆红素可逆转PI的抗增殖和炎症作用，但一氧化碳不能逆转PI的抗增殖和炎症作用。或者，腺病毒介导的HO-1过表达减弱了PI的生长抑制和炎症作用。相反，阻断HO-1活性未能改变PI的抗迁移作用。因此，在人EC中通过ROS-Nrf 2途径诱导HO-1通过产生胆红素抵消PI的抗增殖和炎症作用。针对HO-1的治疗方法可能为预防接受抗逆转录病毒治疗的HIV感染患者的EC功能障碍和血管疾病提供一种新的方法。
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.