Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α
Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α
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DOI：
10.1161/jaha.118.011628
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发表时间：
2019-03-05
影响因子：
5.4
通讯作者：
MacLean, Margaret R.
中科院分区：
文献类型：
--
作者：
Docherty, Craig K.;Nilsen, Margaret;MacLean, Margaret R.
背景——女性患肺动脉高压的风险更大，雌激素及其下游代谢物在该疾病的发病机制中发挥着潜在作用。缺氧诱导因子 1-α (HIF1 α) 是一种促增殖介质，可能参与人类肺动脉高压的发生。雌激素代谢物 2-甲氧基雌二醇 (2ME2) 具有抗增殖特性，也是 HIF1 α 的抑制剂。在这里，我们检查了大鼠和人肺循环中 HIF1 α 信号传导的性别差异，并确定 2ME2 是否可以在体内和体外抑制 HIF1 α。方法和结果 - 在男性和女性远端人肺动脉平滑肌细胞 (hPASMC) 中评估了 HIF1 α 信号传导，并在女性 hPASMC 中研究了 2ME2 的影响。还确定了 2ME2 在肺动脉高压慢性缺氧大鼠（雄性和雌性）模型中的体内作用。与男性相比，女性 hPASMC 中的基础 HIF1 α 蛋白表达较高。与男性相比，女性 hPASMC 中 HIF 抑制因子和脯氨酰羟化酶 2（羟化 HIF 导致蛋白体降解）蛋白水平均显着降低。在体内，2ME2 消除了雄性和雌性大鼠缺氧诱导的肺动脉高压，同时降低了 HIF1 α 的蛋白表达。 2ME2 减少 hPASMC 的增殖并减少 HIF1 α 的基础蛋白表达。此外，2ME2 会引起细胞凋亡并对微管网络造成显着破坏。 结论：女性 hPASMC 中较高的基础 HIF1 α 可能会增加发生肺动脉高压的易感性。这些数据还表明，2ME2 在肺动脉高压中的抗增殖和治疗作用可能涉及抑制 HIF1 α 和/或 PASMC 中的微管破坏。
Background-Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease. Hypoxia-inducible factor-1-alpha (HIF1 alpha) is a pro-proliferative mediator and may be involved in the development of human pulmonary arterial hypertension. The estrogen metabolite 2-methoxyestradiol (2ME2) has antiproliferative properties and is also an inhibitor of HIF1 alpha. Here, we examine sex differences in HIF1 alpha signaling in the rat and human pulmonary circulation and determine if 2ME2 can inhibit HIF1 alpha in vivo and in vitro.Methods and Results-HIF1 alpha signaling was assessed in male and female distal human pulmonary artery smooth muscle cells (hPASMCs), and the effects of 2ME2 were also studied in female hPASMCs. The in vivo effects of 2ME2 in the chronic hypoxic rat (male and female) model of pulmonary hypertension were also determined. Basal HIF1 alpha protein expression was higher in female hPASMCs compared with male. Both factor-inhibiting HIF and prolyl hydroxylase-2 (hydroxylates HIF leading to proteosomal degradation) protein levels were significantly lower in female hPASMCs when compared with males. In vivo, 2ME2 ablated hypoxia-induced pulmonary hypertension in male and female rats while decreasing protein expression of HIF1 alpha. 2ME2 reduced proliferation in hPASMCs and reduced basal protein expression of HIF1 alpha. Furthermore, 2ME2 caused apoptosis and significant disruption to the microtubule network.Conclusions-Higher basal HIF1 alpha in female hPASMCs may increase susceptibility to developing pulmonary arterial hypertension. These data also demonstrate that the antiproliferative and therapeutic effects of 2ME2 in pulmonary hypertension may involve inhibition of HIF1 alpha and/or microtubular disruption in PASMCs.