Department of Respiratory Medicine, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu 221002, P.R. China.
Mol Med Rep. 2019 Sep;20(3):2167-2176. doi: 10.3892/mmr.2019.10482. Epub 2019 Jul 9.
Chronic hypoxia is one of the most common causes of secondary pulmonary hypertension, the mechanisms of which remain unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that inhibit the translation or accelerate the degradation of mRNA. Previous studies have demonstrated that deregulated miRNA expression contributes to various cellular processes including cell apoptosis and proliferation, which are mediated by hypoxia. In the present study, the expression of miR‑98 was identified to be decreased in the lung tissue of a hypoxic pulmonary hypertension (HPH) rat model and pulmonary artery (PA) smooth muscle cells (PASMCs), which was induced by hypoxia. By transfecting miR‑98 mimics into PASMCs, the high expression of miR‑98 inhibited cell proliferation, but upregulated hypoxia‑induced PASMCs apoptosis. However, these effects of miR‑98 mimics on PASMCs were reversed by ALK1 (activin receptor‑like kinase‑1) overexpression. ALK1 was identified as a candidate target of miR‑98. In addition, overexpressing miR‑98 markedly decreased the pulmonary artery wall thickness and the right ventricular systolic pressure in rats induced by hypoxia. These results provided clear evidence that miR‑98 was a direct regulator of ALK1, and that the downregulation of miR‑98 contributed to the pathogenesis of HPH. These results provide a novel potential therapeutic strategy for the treatment of HPH.
慢性缺氧是继发性肺动脉高压最常见的原因之一，其机制尚不清楚。微小 RNA（miRNA）是一种小的非编码 RNA，可抑制 mRNA 的翻译或加速其降解。先前的研究表明，miRNA 表达失调参与了各种细胞过程，包括细胞凋亡和增殖，这些过程是由缺氧介导的。在本研究中，鉴定出 miR-98 在缺氧性肺动脉高压（HPH）大鼠模型和肺动脉平滑肌细胞（PASMC）中的表达降低，这是由缺氧诱导的。通过将 miR-98 模拟物转染到 PASMC 中，高表达的 miR-98 抑制细胞增殖，但上调缺氧诱导的 PASMC 凋亡。然而，miR-98 模拟物对 PASMC 的这些作用被 ALK1（激活素受体样激酶-1）过表达逆转。ALK1 被鉴定为 miR-98 的候选靶标。此外，过表达 miR-98 可显著降低缺氧诱导的大鼠肺动脉壁厚度和右心室收缩压。这些结果提供了明确的证据表明 miR-98 是 ALK1 的直接调节因子，miR-98 的下调有助于 HPH 的发病机制。这些结果为 HPH 的治疗提供了一种新的潜在治疗策略。
