HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants.
HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants.
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DOI：
10.1385/ct:4:3:287
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发表时间：
2004-01-01
影响因子：
3.2
通讯作者：
Agrawal, Krishna C
中科院分区：
文献类型：
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作者：
Mondal, Debasis;Pradhan, Leena;Agrawal, Krishna C
高效抗逆转录病毒治疗（HAART）已显着改善HIV-1感染患者的预后，但与显着的副作用，如糖尿病，动脉粥样硬化和心血管并发症。氧化应激可通过调节促动脉粥样硬化因子和抗动脉粥样硬化因子之间的平衡来破坏内皮稳态。我们假设长期暴露于HAART导致内皮氧化应激和单核细胞募集的激活，这是动脉粥样硬化的早期事件。我们通过监测以下参数研究了HAART药物组合对人主动脉内皮细胞（HAEC）的影响，该药物组合由齐多夫定（一种核苷逆转录酶抑制剂）、依法韦仑（一种非核苷逆转录酶抑制剂）和茚地那韦或奈非那韦这两种蛋白酶抑制剂（PI）中的任一种组成：（1）活性氧（ROS）的产生，（2）单核细胞（Jurkat或U-937）粘附，和（3）细胞粘附分子（CAM）的表达。HAART暴露增加HAECs中ROS的形成。暴露于PI单独和HAART组合中以浓度依赖性方式增加单核细胞与HAEC的粘附。单核细胞粘附HAART暴露HAECs显着增强急性（24小时）暴露于炎性细胞因子，肿瘤坏死因子（TNF）-α或白细胞介素（IL）-1 β，并抑制抗氧化剂N-乙酰半胱氨酸和谷胱甘肽。暴露于HAART增加了细胞间粘附分子-1（ICAM-1）基因表达，同时暴露于TNF-α进一步增加了ICAM-1、血管细胞粘附分子-1（VCAM-1）和内皮-白细胞粘附分子细胞表面蛋白水平。这些研究表明，慢性HAART暴露增加了内皮细胞的氧化应激，并诱导单核细胞募集，这可能最终导致在接受抗逆转录病毒治疗的HIV-1+个体中观察到的心血管疾病。
Highly active antiretroviral therapy (HAART) has significantly improved the prognosis of HIV-1-infected patients but is associated with significant side effects such as diabetes, atherosclerosis, and cardiovascular complications. Oxidative stress can disrupt endothelial homeostasis by dysregulating the balance between pro- and antiatherogenic factors. We hypothesized that chronic exposure to HAART results in endothelial oxidative stress and activation of mononuclear cell recruitment, an early event in atherosclerosis. We studied the effects of HAART drug combinations, consisting of zidovudine, a nucleoside reverse transcriptase inhibitor; efavirenz, a nonnucleoside reverse transcriptase inhibitor; and either of the two protease inhibitors (PIs), indinavir or nelfinavir, on human aortic endothelial cells (HAECs) by monitoring the following parameters: (1) generation of reactive oxygen species (ROS), (2) mono-nuclear cell (Jurkat or U-937) adhesion, and (3) expression of cell adhesion molecules (CAMs). HAART exposure increased ROS formation in HAECs. Exposure to PIs alone and in HAART combinations increased mononuclear cell adhesion to HAECs in a concentration-dependent manner. Mononuclear cell adhesion to HAART-exposed HAECs was significantly enhanced following acute (24-h) exposure to the inflammatory cytokines, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and was suppressed by the antioxidants N-ace-tylcysteine and glutathione. Exposure to HAART increased intercellular adhesion molecule-1 (ICAM-1) gene expression and concomitant exposure to TNF-alpha further increased ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and endothelial-leukocyte adhesion molecule cell surface protein levels. These studies indicate that chronic HAART exposure increases oxidative stress in endothelial cells and induces mononuclear cell recruitment, which may eventually precipitate the cardiovascular diseases observed in HIV-1+ individuals on antiretroviral therapy.