Mondal Debasis, Pradhan Leena, Ali Mussa, Agrawal Krishna C
Department of Pharmacology, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Cardiovasc Toxicol. 2004;4(3):287-302. doi: 10.1385/ct:4:3:287.
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.
高效抗逆转录病毒疗法（HAART）显著改善了HIV-1感染患者的预后，但会引发诸如糖尿病、动脉粥样硬化和心血管并发症等严重副作用。氧化应激可通过破坏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扰乱内皮稳态。我们推测，长期接触HAART会导致内皮氧化应激和单核细胞募集激活，这是动脉粥样硬化的早期事件。我们通过监测以下参数，研究了由齐多夫定（一种核苷类逆转录酶抑制剂）、依非韦伦（一种非核苷类逆转录酶抑制剂）以及两种蛋白酶抑制剂（PIs）茚地那韦或奈非那韦组成的HAART药物组合对人主动脉内皮细胞（HAECs）的影响：（1）活性氧（ROS）的生成；（2）单核细胞（Jurkat或U-937）的黏附；（3）细胞黏附分子（CAMs）的表达。HAART暴露增加了HAECs中ROS的形成。单独暴露于PIs以及暴露于HAART组合中均以浓度依赖的方式增加了单核细胞与HAECs的黏附。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）-1β后，单核细胞与HAART暴露的HAECs的黏附显著增强，并被抗氧化剂N-乙酰半胱氨酸和谷胱甘肽所抑制。暴露于HAART会增加细胞间黏附分子-1（ICAM-1）基因的表达，同时暴露于TNF-α会进一步增加ICAM-1、血管细胞黏附分子-1（VCAM-1）和内皮白细胞黏附分子的细胞表面蛋白水平。这些研究表明，长期HAART暴露会增加内皮细胞中的氧化应激并诱导单核细胞募集，这最终可能促使接受抗逆转录病毒治疗的HIV-1阳性个体出现心血管疾病。
