1 Research Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom; and.
2 Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Am J Respir Cell Mol Biol. 2018 Mar;58(3):320-330. doi: 10.1165/rcmb.2017-0260OC.
Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1β]), which is shared by HIF-1α and AhR. Su reduced HIF-1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.
血管内皮生长因子抑制剂 Sugen 5416（Su）处理的大鼠在缺氧后再恢复到常氧，已成为肺动脉高压（PAH）的一种广泛使用的模型。然而，Su 加剧肺动脉高压的机制尚不清楚。我们研究了 Su 在人肺动脉平滑肌细胞（hPASMC）和女性 PAH 患者的血管外生内皮细胞（BOEC）中激活芳香烃受体（AhR）的作用。我们还研究了 AhR 对肺中芳香酶和雌激素水平的影响。蛋白和 mRNA 分析表明，CYP1A1 在 Su/缺氧（Su/Hx）大鼠的肺部高度诱导。AhR 拮抗剂 CH223191（8mg/kg/天）在体内逆转了该模型中 PAH 的发展，并使肺 CYP1A1 表达正常化。Su/Hx 大鼠的肺芳香酶和雌激素水平增加也被 CH223191 正常化，AhR 核转位蛋白（ARNT[HIF-1β]）也是如此，它与 HIF-1α 和 AhR 共享。Su 降低了 hPASMC 中的 HIF-1α 表达。Su 在 BOEC 中诱导增殖，并增加人肺微血管 EC 的凋亡，还诱导 AhR 在 hPASMC 中转位到核内。在常氧条件下，hPASMC 对 Su 不增殖。然而，当在低氧（1%）下生长时，Su 诱导 hPASMC 增殖。在低氧与 Su 联合作用下，Su 在 PAH 患者的 hPASMC 和 BOEC 中具有增殖作用，Su/Hx 诱导的大鼠 PAH 可能是由 AhR 诱导的 CYP1A1、ARNT 和芳香酶引起的。AhR 抑制可能是治疗肺动脉高压的一种新方法。
