5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase promotes pulmonary arterial smooth muscle cell proliferation via the Ras signaling pathway.

IF 5 2区 生物学 Q2 CELL BIOLOGY American journal of physiology. Cell physiology Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI:10.1152/ajpcell.00262.2024
Xiaofan Shi, Qian Ma, Yuqing Huo, Yunchao Su
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Abstract

Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway.NEW & NOTEWORTHY Our findings highlight the important role of ATIC in the PASMC proliferation of pulmonary vascular remodeling through its modulation of the Ras signaling pathway and its regulation by transcription factors MYC, EGR1, and SP1. ATIC's modulation of Ras signal pathway represents a novel mechanism contributing to PAH development.

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--------ATIC 通过 Ras 信号通路促进肺动脉平滑肌细胞增殖。
肺动脉高压(PAH)是一种使人衰弱的血管疾病,其特点是肺动脉平滑肌细胞(PASMC)增殖和胶原合成异常,导致血管重塑和肺血管阻力升高。本研究调查了 5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰转移酶/肌苷酸单磷酸环醇酶(ATIC)在 PAH 患者 PASMC 细胞增殖和胶原合成中的关键作用。我们在这里发现,在 MCT 诱导的 PAH 大鼠模型和缺氧诱导的 PAH 小鼠模型肺中,以及 PDGF 刺激的 PASMCs 中,ATIC 水平明显升高。抑制 ATIC 可减少血小板衍生生长因子(PDGF)诱导的 PASMCs 细胞增殖和胶原 I 合成。相反,过表达或敲除 ATIC 会显著促进或抑制 PASMCs 中 Ras 和 ERK 的活化、细胞增殖和胶原合成。此外,ATIC 的缺失可减轻缺氧诱导的 PAH 小鼠肺部的 Ras 激活。此外,抑制 Ras 可减轻 ATIC 过表达和 PDGF 诱导的胶原合成和 PASMC 增殖。值得注意的是,我们发现转录因子 MYC、EGR1 和 SP1 直接与 ATIC 基因启动子结合并调控 ATIC 的表达。这些结果首次证明 ATIC 通过 Ras 信号通路促进肺血管重塑过程中 PASMC 的增殖。
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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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