Department of Breast Sugery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
Department of Ultrasonography, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
Microvasc Res. 2019 Jul;124:43-50. doi: 10.1016/j.mvr.2019.03.001. Epub 2019 Mar 7.
Pulmonary arterial hypertension (PAH) is a devastating and fatal vascular disease for which currently there is no satisfying therapy available. Excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) contributes significantly to PAH pathogenesis. In this study, we found that miR-205-5p was lowly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Restoration of miR-205-5p suppressed PASMCs proliferation. In contrast, molecule interacting with CasL 2 (MICAL2) was highly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Overexpression of MICAL2 promoted cell proliferation. Furthermore, miR-205-5p inhibited MICAL2 expression levels by targeting the MICAL2 3' untranslated region. In addition, MICAL2 activated ERK1/2 signaling in PASMCs and ERK1/2 inhibitor blocked MICAL2-mediated-promotion effect on PASMCs proliferation. These results demonstrated that miR-205-5p suppressed PASMCs proliferation by targeting MICAL2, which activated ERK1/2 signaling. Therefore, miR-205-5p/MICAL2/Erk1/2 may serve as an ideal therapeutic target to PAH treatment.
肺动脉高压（PAH）是一种破坏性和致命性的血管疾病，目前尚无令人满意的治疗方法。肺动脉平滑肌细胞（PASMCs）的过度增殖对 PAH 的发病机制有重要贡献。在本研究中，我们发现 miR-205-5p 在低氧诱导的 PAH 小鼠模型和低氧处理的 PASMCs 中低表达。miR-205-5p 的恢复抑制了 PASMCs 的增殖。相反，分子相互作用 CasL 2（MICAL2）在低氧诱导的 PAH 小鼠模型和低氧处理的 PASMCs 中高表达。MICAL2 的过表达促进细胞增殖。此外，miR-205-5p 通过靶向 MICAL2 的 3'非翻译区抑制 MICAL2 的表达水平。此外，MICAL2 在 PASMCs 中激活 ERK1/2 信号通路，ERK1/2 抑制剂阻断 MICAL2 对 PASMCs 增殖的促进作用。这些结果表明，miR-205-5p 通过靶向 MICAL2 抑制 PASMCs 的增殖，而 MICAL2 激活了 ERK1/2 信号通路。因此，miR-205-5p/MICAL2/Erk1/2 可能成为治疗 PAH 的理想治疗靶点。
