Wang Jia, Xuan Bing, Song Baomei, Wang Ting, Lan Cong, Guo Wei, Yang Yongjian, Sun Xiongshan
Department of Cardiology, The General Hospital of Western Theater Command, 270 Tianhui Rd., Rongdu Ave., Jinniu, Chengdu, 610083, Sichuan, China.
Department of Pharmacy, Stomatological Hospital of Chongqing Medical University, Chongqing, 400015, China.
Mol Cell Biochem. 2025 Jun;480(6):3799-3812. doi: 10.1007/s11010-025-05217-y. Epub 2025 Feb 7.
Myotubularin-related protein 7 (MTMR7) represses proliferation in several cell types. However, the role of MTMR7 in pulmonary arterial smooth muscle cells (PASMCs) and pulmonary hypertension (PH) is unknown. The present study aimed to explore the role of MTMR7 in PH, as well as in the proliferation and migration of PASMCs. A monocrotaline (MCT)-induced PH mouse model was established. Mtmr7-transgenic (Mtmr7-Tg) mice and an adenovirus carrying the Mtmr7 vector (Ad-Mtmr7) were used to achieve MTMR7 overexpression in vivo and in vitro, respectively. Ultrasound and morphological analyses were used to evaluate the severity of PH. Cell counting kit-8 (CCK-8) and Ki-67 immunofluorescence staining were used to assess the proliferation of PASMCs. Wound-healing and transwell assays were used to assess cell migration. MTMR7 was upregulated in hypoxia-stimulated PASMCs and pulmonary arteries of MCT-treated mice. When compared with wild-type mice, PH-associated symptoms were significantly ameliorated in Mtmr7-Tg mice after MCT treatment when compared to wild-type mice. MTMR7 overexpression suppressed the proliferation and migration of PASMCs induced by hypoxia. Further experiments revealed that MTMR7 inhibited the phosphorylation levels of ERK1/2 and STAT3 both in vivo and in vitro. Restoring either ERK1/2 or STAT3 eliminated the protective role of MTMR7 against PH. Additionally, restoring ERK1/2 also reversed MTMR7-mediated STAT3 dephosphorylation. Our study highlights the inhibitory role of MTMR7 in PH and in the proliferation and migration of PASMCs and thus provides a novel potent therapeutic strategy for treating PH.
与肌管素相关的蛋白7（MTMR7）在多种细胞类型中抑制增殖。然而，MTMR7在肺动脉平滑肌细胞（PASMCs）和肺动脉高压（PH）中的作用尚不清楚。本研究旨在探讨MTMR7在PH以及PASMCs增殖和迁移中的作用。建立了野百合碱（MCT）诱导的PH小鼠模型。分别使用Mtmr7转基因（Mtmr7-Tg）小鼠和携带Mtmr7载体的腺病毒（Ad-Mtmr7）在体内和体外实现MTMR7的过表达。采用超声和形态学分析评估PH的严重程度。使用细胞计数试剂盒-8（CCK-8）和Ki-67免疫荧光染色评估PASMCs的增殖。采用伤口愈合试验和Transwell试验评估细胞迁移。在缺氧刺激的PASMCs和MCT处理小鼠的肺动脉中，MTMR7上调。与野生型小鼠相比，MCT处理后的Mtmr7-Tg小鼠的PH相关症状明显改善。MTMR7过表达抑制了缺氧诱导的PASMCs的增殖和迁移。进一步的实验表明，MTMR7在体内和体外均抑制ERK1/2和STAT3的磷酸化水平。恢复ERK1/2或STAT3均可消除MTMR7对PH的保护作用。此外，恢复ERK1/2也可逆转MTMR7介导的STAT3去磷酸化。我们的研究突出了MTMR7在PH以及PASMCs增殖和迁移中的抑制作用，从而为治疗PH提供了一种新的有效治疗策略。
