2-甲氧雌二醇通过microRNAs缓解慢性间歇低氧诱导的肺动脉高压的机制研究

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a harmful disease with high incidence. Chronic intermittent hypoxia (CIH) is the important character of OSAHS and inclined to cause pulmonary arterial hypertension (PAH). It exists sex differences in OSAHS and PAH. Estradiol-2 (E2) are involed in the protection process of OSAHS induced PAH. It is very important to explore the mechanism of how E2 protect CIH-PAH. 2-methoxyestradiol (2-ME), metabolite of E2, could suppress cell proliferation and angiogenesis of pulmonary artery smooth muscle cells (PASMC). According to our previous study, we provided the hypothesis that elevation of 2-ME contributed to protect cell proliferation and angiogenesis of PASMC through the pathway of miR-223/IGF-1R/ PARP-1, miR-466b-1/IGF-1 and miR-204/RUNX2 under the condition of CIH. Our project intended to use the model of CIH and gene interference technology, exploring the molecular mechanism of how 2-ME maintains PASMC stability through the above miRNAs and target protein from the genic level to systemic level. Our project is aimed to clarify whether HIF-1αand PARP-1 are the point of junction of miRNAs and their targeted protein, reveal the mechanism of 2-ME improving CIH induced PAH, and provide new target for the prevention and therapeutic clues for PAH.

OSAHS发病率高，危害大，慢性间歇低氧（ CIH ）是其重要特征，易诱发肺动脉高压（PAH）。因此，探索OSAHS相关CIH-PAH的机制意义重大。OSAHS和PAH存在性别差异，雌二醇参与保护作用；雌激素改善PAH的机制是个重要问题。我们发现雌二醇代谢产物2-甲氧雌二醇（ 2-ME）能抑制肺动脉平滑肌细胞（PASMC）增殖，结合前期工作，提出假说：CIH时外源性给予2-ME可通过调节miR-223/IGF-1R或PARP-1、miR-466b-1/IGF-1、miR-204/RUNX2通路改善PASMC增殖和凋亡异常。本课题拟利用CIH模型，采用基因干扰等技术，从基因到系统水平，探讨2-ME调控miRNAs及靶蛋白缓解PASMC异常的分子机制；明确HIF-1α和PARP-1是miRNAs及靶蛋白交互作用的连接点，揭示2-ME改善CIH-PAH的机制，为PAH的预防和治疗提供新靶点。

OSAHS发病率高，危害大，慢性间歇低氧（ CIH ）是其重要特征，易诱发肺动脉高压 （PAH）。因此，探索OSAHS相关CIH-PAH的机制意义重大。OSAHS和PAH存在性别差异，雌二醇参与保护作用；雌激素改善PAH的机制是个重要问题。我们发现雌二醇代谢产物2-甲氧雌二醇（ 2-ME）能抑制肺动脉平滑肌细胞（PASMC）增殖，结合前期工作，提出假说：CIH时外源性给予2-ME可通过调节miR-223/IGF-1R或PARP-1、miR-466b-1/IGF-1、miR-204 /RUNX2通路改善PASMC增殖和凋亡异常。本课题拟利用CIH模型，采用基因干扰等技术，从基因到系统水平，探讨2-ME调控miRNAs及靶蛋白缓解PASMC异常的分子机制；明确HIF-1α 是miRNAs及靶蛋白交互作用的连接点，揭示2-ME改善CIH-PAH的机制，为PAH的预防和治疗提供新靶点。本研究发现，成年的Sprague-Dawley大鼠暴露于CIH，可有效诱导肺动脉高压的形成。通过2-甲氧基雌二醇（2-Me）处理，可有效控制PAH。结果表明2-Me处理可降低CIH大鼠肺血管生成的进程，并减轻CIH在肺动脉平滑肌细胞（PASMC）中的增殖，细胞迁移和活性氧的形成。 CIH降低了miR-223的表达，而2-Me在体内和体外均可逆转miR-223的下调。此外，miR-223抑制剂消除了在PASMCs中观察到的2-Me的抗血管生成作用，而miR-223模仿物则增强了其抗血管生成作用。这些发现表明，miR-223在CIH诱导PH的过程中起重要作用，而2-Me可能通过上调miR-223逆转CIH诱导的PH。