Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, China; Research Center for Drug Safety Evaluation of Hainan Province, Hainan Medical University, Haikou 571199, Hainan, China.
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, Hunan, China.
Life Sci. 2020 Aug 15;255:117822. doi: 10.1016/j.lfs.2020.117822. Epub 2020 May 23.
Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) are regarded as the primary factors resulting in pulmonary arterial remodeling in pulmonary hypertension (PH). Myeloid ecotropic viral integration site 1 (MEIS1) has been positioned as a negative cardiomyocyte cell cycle regulator and regulates proliferation of multiple kinds of cancer cells. Whether MESI1 is involved in the proliferation and migration of PASMCs deserves to be identified.
Sprague Dawley rats were exposed to hypoxia condition (10% O) for 4 weeks to induce PH and primary rat PASMCs were cultured in hypoxia condition (3% O) for 48 h to induce proliferation and migration. Immunohistochemistry, immunofluorescence, reverse transcription PCR and Western blot analysis were performed to detect the expressions of target mRNAs and proteins. EDU, CCK8 and wound healing assays were conducted to measure the proliferation and migration of PASMCs.
Hypoxia down-regulated the expression of MEIS1 (both mRNA and protein) in pulmonary arteries and PASMCs. Over-expression of MEIS1 inhibited the proliferation and migration of PASMCs afforded by hypoxia. In contrast, knockdown of MEIS1 under normoxia condition like hypoxia induced the proliferation and migration of PASMCs. MEIS1 mediated hypoxia-induced the proliferation and migration of PASMCs via METTL14/MEIS1/p21 signaling.
The present study revealed that MEIS1 regulated the proliferation and migration of PASMCs during hypoxia-induced PH. Thus, MEIS1 may be a potential target for PH therapy.
肺动脉平滑肌细胞（PASMCs）的增殖和迁移被认为是导致肺动脉高压（PH）中肺血管重构的主要因素。髓样细胞特异性增强子结合蛋白 1（MEIS1）被定位为负性心肌细胞细胞周期调节剂，并调节多种癌细胞的增殖。MEIS1 是否参与 PASMCs 的增殖和迁移值得研究。
将 Sprague Dawley 大鼠置于低氧环境（10% O2）中 4 周以诱导 PH，并将原代大鼠 PASMCs 置于低氧环境（3% O2）中培养 48 小时以诱导增殖和迁移。采用免疫组织化学、免疫荧光、反转录 PCR 和 Western blot 分析检测靶基因的表达。通过 EDU、CCK8 和划痕愈合实验检测 PASMCs 的增殖和迁移。
低氧下调肺动脉和 PASMCs 中 MEIS1 的表达（mRNA 和蛋白）。过表达 MEIS1 抑制低氧诱导的 PASMCs 的增殖和迁移。相反，在常氧条件下敲低 MEIS1 可诱导 PASMCs 的增殖和迁移，与低氧诱导的作用类似。MEIS1 通过 METTL14/MEIS1/p21 信号通路介导低氧诱导的 PASMCs 的增殖和迁移。
本研究揭示了 MEIS1 调节低氧诱导 PH 时 PASMCs 的增殖和迁移。因此，MEIS1 可能是 PH 治疗的潜在靶点。
