Wang Xinwen, Chai Hong, Lin Peter H, Yao Qizhi, Chen Changyi
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM390, Houston, TX 77030, USA.
Am J Pathol. 2009 Mar;174(3):771-81. doi: 10.2353/ajpath.2009.080157. Epub 2009 Feb 13.
The objective of this study was to determine the effects of highly active antiretroviral therapy (HAART) drugs on pulmonary endothelial function. Porcine pulmonary arteries or human pulmonary arterial endothelial cells (HPAECs) were incubated with eight HAART drugs [ritonavir, indinavir, lopinavir, zidovudine (AZT), abacavir, stavudine, didanosine (ddI), and lamivudine] individually or in combination [three HAART drugs (3-plex; indinavir, stavudine, and ddI)] at their clinical plasma concentrations for 24 hours. Endothelium-dependent vasorelaxation in response to bradykinin was reduced significantly by the ritonavir in a concentration-dependent manner. Five other HAART drugs (indinavir, lamivudine, abacavir, AZT, and ddI) and the 3-plex significantly also impaired endothelium-dependent vasorelaxation in response to bradykinin. Five HAART drugs (ritonavir, indinavir, lamivudine, abacavir, and AZT) significantly decreased endothelial nitric oxide synthase (eNOS) expression and increased superoxide anion levels in both vessels and HPAECs. Furthermore, both ritonavir and AZT substantially activated ERK2 in HPAECs. Additionally, the antioxidants ginsenoside Rb1 and ginkgolide A effectively reversed HAART drug-induced vasomotor dysfunction and eNOS down-regulation. Inhibition of ERK1/2 also partially blocked ritonavir- and AZT-induced down-regulation of eNOS and vasomotor dysfunction. Thus, HAART drugs significantly impair endothelial functions of porcine pulmonary arteries and HPAECs, which may be mediated by eNOS down-regulation, oxidative stress, and ERK1/2 activation. These findings suggest that HAART drugs may contribute to the high incidence of pulmonary artery hypertension in human immunodeficiency virus-infected patients.
本研究的目的是确定高效抗逆转录病毒疗法（HAART）药物对肺内皮功能的影响。将猪肺动脉或人肺动脉内皮细胞（HPAECs）与八种HAART药物[利托那韦、茚地那韦、洛匹那韦、齐多夫定（AZT）、阿巴卡韦、司他夫定、去羟肌苷（ddI）和拉米夫定]单独或联合使用[三种HAART药物（三联组合；茚地那韦、司他夫定和ddI）]，在其临床血浆浓度下孵育24小时。利托那韦以浓度依赖性方式显著降低了对缓激肽的内皮依赖性血管舒张。其他五种HAART药物（茚地那韦、拉米夫定、阿巴卡韦、AZT和ddI）以及三联组合也显著损害了对缓激肽的内皮依赖性血管舒张。五种HAART药物（利托那韦、茚地那韦、拉米夫定、阿巴卡韦和AZT）显著降低了血管和HPAECs中内皮型一氧化氮合酶（eNOS）的表达，并增加了超氧阴离子水平。此外，利托那韦和AZT均显著激活了HPAECs中的ERK2。此外，抗氧化剂人参皂苷Rb1和银杏内酯A有效逆转了HAART药物诱导的血管舒缩功能障碍和eNOS下调。抑制ERK1/2也部分阻断了利托那韦和AZT诱导的eNOS下调和血管舒缩功能障碍。因此，HAART药物显著损害猪肺动脉和HPAECs的内皮功能，这可能由eNOS下调、氧化应激和ERK1/2激活介导。这些发现表明，HAART药物可能导致人类免疫缺陷病毒感染患者肺动脉高压的高发病率。
