miR-182-3p/Myadm contribute to pulmonary artery hypertension vascular remodeling via a KLF4/p21-dependent mechanism
miR-182-3p/Myadm contribute to pulmonary artery hypertension vascular remodeling via a KLF4/p21-dependent mechanism
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miR-182-3p/Myadm 通过 KLF4/p21 依赖性机制促进肺动脉高压血管重塑
DOI：
10.7150/thno.44687
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Du, Guanhua
中科院分区：
文献类型：
--
作者：
Sun, Lan;Lin, Peirong;Du, Guanhua
理论基础：仍有必要研究microRNAs及其靶点在肺动脉高压(PAH)血管重塑发病机制中的作用。我们最近发现髓系miR-182-3p及其新靶点--髓系相关分化标记物(Myadm)与血管重塑有关。本研究旨在探讨miR-182-3p/Myadm在PAH血管重构中的作用及其分子机制。方法：检测PAH患者和实验性啮齿动物模型miR-182-3p/Myadm的表达谱。采用基因敲入和基因敲除的功能丧失和功能获得研究，结合蛋白质组学技术和全基因组芯片-SEQ来确定野百合碱(MCT)诱导的PAH反应中miR-182-3p/Myadm的下游靶点。结果：在PAH患者和实验性啮齿动物模型中，miR-182-3p/Myadm的表达发生了改变。MiR-182-3p抑制剂和Myadm的过度表达均促进了MCT诱导的PAH大鼠的病理进程。相反，miR-182-3p模拟和Myadm基因敲除减轻了MCT诱导的PAH大鼠血流动力学和心肺系统结构的变化。Myadm通过转录因子Krüppel-like factor4(KLF4)转位到胞浆内，改变细胞周期蛋白激酶抑制物(p21/Cip1)的表达，从而介导PASMCs的增殖。结论：miR-182-3p在PAH中具有预后和治疗意义，为髓系miR-182-3p/Myadm/KLF4/p21轴在PAH血管重构中的调控提供了新的模型。
Rationale: There is a continued need for investigating the roles of microRNAs and their targets on the pathogenesis of pulmonary arterial hypertension (PAH) vascular remodeling. We recently identified the association of myeloid miR-182-3p and its new target, Myeloid-Associated Differentiation Marker (Myadm), with vascular remodeling. Here, we aimed to determine the role of miR-182-3p/Myadm on PAH vascular remodeling and the underlying molecular mechanism. Methods: The miR-182-3p/Myadm expression profiles were detected in PAH patients and experimental rodent models. Loss-of-function and gain-of-function studies using gene knock-in or gene knock-out and the combinations of the proteomic technology and genome-wide ChIP-Seq were employed to determine the downstream targets of miR-182-3p/Myadm in response to monocrotaline (MCT)-induced PAH. Results: The miR-182-3p/Myadm expression was altered in PAH patients and experimental rodent models. Both miR-182-3p inhibitor and overexpression of Myadm augmented the pathological progression in rats in response to MCT-induced PAH. In contrast, miR-182-3p mimic and Myadm gene knockout attenuated the changes in the hemodynamics and structure of the cardio-pulmonary system in MCT-induced PAH in rats. Myadm mediated the proliferation of pulmonary artery smooth muscle cells (PASMCs) by altering the cell cycle kinase inhibitor (p21/Cip1) expression through the transcription factor Krüppel-like factor 4 (KLF4) translocation into the cytoplasm. Conclusion: Our findings indicate the prognostic and therapeutic significance of miR-182-3p in PAH and provide a new regulatory model of the myeloid-derived miR-182-3p/Myadm/KLF4/p21 axis in PAH vascular remodeling.