HIV gp120 诱导肿瘤坏死因子-α激活的猪和人内皮细胞功能障碍。
HIV gp120 induces endothelial dysfunction in tumour necrosis factor-alpha-activated porcine and human endothelial cells.
机构信息
Molecular Surgeon Research Center, Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
出版信息
Cardiovasc Res. 2010 Jul 15;87(2):366-74. doi: 10.1093/cvr/cvq013. Epub 2010 Jan 18.
AIMS
The aim of this study was to determine direct effects and potential molecular mechanisms of HIV gp120, a viral envelope glycoprotein, on endothelial function.
METHODS AND RESULTS
Fresh porcine coronary artery rings and human coronary artery endothelial cells (HCAECs) were treated with recombinant HIV gp120 for 16 h with or without pretreatment with tumour necrosis factor-alpha (TNF-alpha) (8 h). With a myograph tension analysis, HIV gp120 with TNF-alpha pretreatment significantly decreased endothelium-dependent vasorelaxation in response to bradykinin in porcine coronary artery rings compared with untreated control vessels. In addition, HIV gp120 with TNF-alpha pretreatment significantly reduced endothelial nitric oxide synthase (eNOS) expression-both mRNA and protein levels-in porcine coronary artery rings and HCAECs compared with untreated controls. Furthermore, TNF-alpha pretreatment substantially increased intercellular adhesion molecule-1 (ICAM-1) expression in artery rings and HCAECs. Anti-gp120 or anti-ICAM-1 antibody significantly blocked these effects of HIV gp120. Silencing of ICAM-1 by siRNA oligonucleotides significantly blocked the effect of gp120 on eNOS downregulation in TNF-alpha-pretreated HCAECs.
CONCLUSION
HIV gp120 and TNF-alpha synergistically reduce eNOS expression and cause endothelial dysfunction in both porcine coronary arteries and HCAECs. ICAM-1 induced by TNF-alpha pretreatment may mediate HIV gp120-induced endothelial dysfunction, which suggests a novel molecular mechanism of HIV gp120-ICAM-1 interaction inducing endothelial dysfunction.
目的
本研究旨在确定 HIV gp120（一种病毒包膜糖蛋白）对血管内皮功能的直接作用及其潜在的分子机制。
方法和结果
用重组 HIV gp120 处理新鲜猪冠状动脉环和人冠状动脉内皮细胞（HCAEC）16 小时，并用或不用肿瘤坏死因子-α（TNF-α）预处理 8 小时。通过肌电图张力分析，与未经处理的对照血管相比，用 TNF-α预处理的 HIV gp120 显著降低了猪冠状动脉环对缓激肽的内皮依赖性血管舒张反应。此外，与未经处理的对照相比，用 TNF-α预处理的 HIV gp120 显著降低了猪冠状动脉环和 HCAEC 中的内皮型一氧化氮合酶（eNOS）表达-无论是 mRNA 还是蛋白水平。此外，TNF-α预处理在动脉环和 HCAEC 中显著增加了细胞间黏附分子-1（ICAM-1）的表达。抗 gp120 或抗 ICAM-1 抗体显著阻断了 HIV gp120 的这些作用。用 siRNA 寡核苷酸沉默 ICAM-1 显著阻断了 gp120 在 TNF-α预处理的 HCAEC 中对 eNOS 下调的作用。
结论
HIV gp120 和 TNF-α协同作用降低 eNOS 表达，导致猪冠状动脉和 HCAEC 内皮功能障碍。TNF-α预处理诱导的 ICAM-1 可能介导 HIV gp120 诱导的内皮功能障碍，这表明 HIV gp120-ICAM-1 相互作用诱导内皮功能障碍的新分子机制。
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