Dihydroartemisinin Attenuates Hypoxia-Induced Pulmonary Hypertension Through the ELAVL2/miR-503/PI3K/AKT Axis.
Dihydroartemisinin Attenuates Hypoxia-Induced Pulmonary Hypertension Through the ELAVL2/miR-503/PI3K/AKT Axis.
复制标题
双氢青蒿素通过ELAVL 2/miR-503/PI 3 K/AKT轴减轻缺氧诱导的肺动脉高压
DOI：
10.1097/fjc.0000000000001271
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发表时间：
2022-07-01
影响因子：
3
通讯作者：
Wang, Liangxing
中科院分区：
文献类型：
--
作者：
Cai, Haijian;Fan, Shiqian;Cai, Luqiong;Zhu, Lin;Zhao, Zhucheng;Li, Yaozhe;Yao, Yizhu;Huang, Xiaoying;Wang, Liangxing
二氢青蒿素（DHA）是从传统中药青蒿中提取的青蒿素的活性形式，用于治疗疟疾。已有研究表明DHA对肺动脉高压（PH）有治疗作用，但其具体机制尚未完全阐明。在这项研究中，建立了缺氧诱导的PH小鼠模型，并给予DHA作为治疗干预。采用细胞计数试剂盒-8和5-乙炔基-2 ′-脱氧尿苷（5-ethynyl-2′-deoxyuridine，EdU）细胞增殖检测试剂盒检测缺氧和常氧条件下培养的肺动脉平滑肌细胞增殖情况。采用Transwell迁移小室法检测同一细胞模型的细胞迁移情况。与体内治疗效果一致，DHA抑制缺氧诱导的细胞增殖和迁移。通过小鼠肺组织高通量测序，筛选出胚胎致死性异常视觉样蛋白2（ELAVL 2）作为PH的关键RNA结合蛋白，DHA通过促进ELAVL 2的表达和调节miR-503/PI 3 K/AKT通路抑制肺动脉平滑肌细胞增殖和迁移。通过RNA结合蛋白免疫沉淀试验验证了ELAVL 2与pre-miR-503之间的结合关系。综上所述，我们首次提出DHA通过ELAVL 2/miR-503/PI 3 K/AKT途径减轻PH，这可能为PH的新治疗策略提供依据。
Dihydroartemisinin (DHA) is an active form of artemisinin extracted from the traditional Chinese medicine Artemisia annua, which is used to treat malaria. Previous studies have shown that DHA has a therapeutic effect on pulmonary hypertension (PH), but its specific mechanism has not been fully elucidated. In this study, a hypoxia-induced PH mouse model was established and DHA was administered as a therapeutic intervention. We measured hemodynamics and right ventricular hypertrophy and observed hematoxylin and eosin staining of lung tissue sections, proving the therapeutic effect of DHA on PH. Furthermore, cell counting kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation assay kit were performed to examine cell proliferation of pulmonary artery smooth muscle cells cultured in hypoxia or in normoxia. Transwell migration chamber assay was performed to examine cell migration of the same cell model. Consistent with the therapeutic effect in vivo, DHA inhibited hypoxia-induced cell proliferation and migration. Through high-throughput sequencing of mouse lung tissue, we screened embryonic lethal abnormal vision-like 2 (ELAVL2) as a key RNA binding protein in PH. Mechanistically, DHA inhibited the proliferation and migration of pulmonary artery smooth muscle cells by promoting the expression of ELAVL2 and regulating the miR-503/PI3K/AKT pathway. The binding relationship between ELAVL2 and pre-miR-503 was verified by RNA binding protein immunoprecipitation assay. In conclusion, we first propose that DHA alleviates PH through the ELAVL2/miR-503/PI3K/AKT pathway, which may provide a basis for new therapeutic strategies of PH.