Qian Zhengjiang, Li Yanjiao, Chen Jidong, Li Xiang, Gou Deming
Shenzhen Key Laboratory of Microbial Genetic Engineering, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong China;
The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China; and.
Am J Physiol Cell Physiol. 2017 Oct 1;313(4):C380-C391. doi: 10.1152/ajpcell.00061.2017. Epub 2017 Jul 12.
MicroRNAs (miRNAs) can regulate the proliferative status of pulmonary artery smooth muscle cells (PASMCs), which is a core factor modulating pulmonary vascular remodeling diseases, such as atherosclerosis and pulmonary arterial hypertension (PAH). Our previous work has shown that miR-4632, a rarely reported miRNA, is significantly downregulated in platelet-derived growth factor (PDGF)-BB-stimulated human pulmonary artery smooth muscle cells (HPASMCs), yet its cell function and the underlying molecular mechanisms remain to be elucidated. Here, we find that miR-4632 is highly expressed in HPASMCs and its expression significantly decreased in response to different stimuli. Functional studies revealed that miR-4632 inhibited proliferation and promoted apoptosis of HPASMCs but had no effects on cell contraction and migration. Furthermore, the cJUN was identified as a direct target gene of miR-4632, while knockdown of cJUN was necessary for miR-4632-mediated HPASMC proliferation and apoptosis. In addition, the downregulation of miR-4632 by PDGF-BB was found to associate with histone deacetylation through the activation of PDGF receptor/phosphatidylinositol 3'-kinase/histone deacetylase 4 signaling. Finally, the expression of miR-4632 was reduced in the serum of patients with PAH. Overall, our results suggest that miR-4632 plays an important role in regulating HPASMC proliferation and apoptosis by suppression of cJUN, providing a novel therapeutic miRNA candidate for the treatment of pulmonary vascular remodeling diseases. It also implies that serum miR-4632 has the potential to serve as a circulating biomarker for PAH diagnosis.
微小RNA（miRNA）可调节肺动脉平滑肌细胞（PASMC）的增殖状态，而PASMC的增殖状态是调节诸如动脉粥样硬化和肺动脉高压（PAH）等肺血管重塑疾病的核心因素。我们之前的研究表明，miR-4632这种鲜有报道的miRNA，在血小板衍生生长因子（PDGF）-BB刺激的人肺动脉平滑肌细胞（HPASMC）中显著下调，但其细胞功能及潜在分子机制仍有待阐明。在此，我们发现miR-4632在HPASMC中高表达，且其表达会因不同刺激而显著降低。功能研究显示，miR-4632抑制HPASMC的增殖并促进其凋亡，但对细胞收缩和迁移无影响。此外，cJUN被鉴定为miR-4632的直接靶基因，而敲低cJUN对于miR-4632介导的HPASMC增殖和凋亡是必要的。另外，发现PDGF-BB导致的miR-4632下调与通过激活PDGF受体/磷脂酰肌醇3'-激酶/组蛋白脱乙酰基酶4信号通路引起的组蛋白去乙酰化有关。最后，PAH患者血清中miR-4632的表达降低。总体而言，我们的结果表明，miR-4632通过抑制cJUN在调节HPASMC增殖和凋亡中发挥重要作用，为肺血管重塑疾病的治疗提供了一种新的治疗性miRNA候选物。这也意味着血清miR-4632有潜力作为PAH诊断的循环生物标志物。
