目的 探究YTH结构域家族蛋白3（YTHDF3）在肺动脉高压（PH）中的作用及其潜在的临床意义。 方法 细胞荧光与Western blot检测YTHDF3在人肺动脉平滑肌细胞（HPASMCs）和PH患者肺组织中的表达水平；病理染色和组织荧光整体评估大鼠肺动脉管壁重塑程度与YTHDF3表达和定位；生信分析探索PH中YTHDF3下游调控通路。 结果 YTHDF3在肺动脉高压患者肺动脉组织以及体外缺氧处理的HPASMCs中表达上调；随着PH模型大鼠的肺动脉血管重塑，YTHDF3在模型大鼠的肺动脉中层表达上调；人水平组学数据同样验证YTHDF3在PH组表达上调，并可能通过调控凋亡等相关通路影响肺动脉高压的发生发展。 结论 YTHDF3富集于肺动脉高压重塑的肺动脉平滑肌中层，通过调节平滑肌细胞凋亡等通路参与肺动脉高压的发生和发展，具有相当的临床转化潜力。
Objective To explore the expression of YTH domain-containing family protein 3 (YTHDF3) in pulmonary hypertension (PH) and evaluate its potential clinical significance. Methods The expression levels of YTHDF3 in human pulmonary arterial smooth muscle cells (HPASMCs) and lung tissues from patients with PH were detected using cellular immunofluorescence and Western blot analysis. Histopathological staining and tissue-wide fluorescence imaging was employed to evaluate the extent of pulmonary arterial wall remodeling and the expression and localization of YTHDF3 in rat models. Bioinformatic analysis was further conducted to explore the downstream regulatory pathways of YTHDF3 in PH. Results YTHDF3 expression upregulated in the pulmonary arterial tissues of patients with PH and in hypoxia-treated HPASMCs in vitro. More importantly, concomitant with the pathological remodeling of pulmonary arteries in a rat model of PH, YTHDF3 expression increased within the medial layer of these vessels. Consistent with these findings, human bulk omics data further confirmed the upregulation of YTHDF3 in PH samples and suggested its potential role in influencing the pathogenesis and progression of pulmonary hypertension, possibly through the regulation of apoptosis-related pathways. Conclusions YTHDF3 is enriched in the remodeled medial layer of pulmonary arteries in PH, where it contributes to the pathogenesis and progression of PH by regulating pathways such as smooth muscle cell apoptosis, demonstrating significant clinical application potential.
[1] Humbert M, Sitbon O, Guignabert C, et al. Treatment of pulmonary arterial hypertension: recent progress and a look to the future [J]. Lancet Respir Med, 2023, 11(9): 804-819. DOI:10.1016/s2213-2600(23)00264-3.
[2] Luna-López R, Ruiz Martín A, Escribano Subías P. Pulmonary arterial hypertension [J]. Med Clin (Barc), 2022, 158(12): 622-629. DOI:10.1016/j.medcli.2022.01.003.
[3] Thenappan T, Ormiston ML, Ryan JJ, et al. Pulmonary arterial hypertension: pathogenesis and clinical management [J]. Bmj, 2018, 360: j5492. DOI:10.1136/bmj.j5492.
[4] Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension [J]. Eur Respir J, 2019, 53(1). DOI:10.1183/13993003. 01913-2018.
[5] Young KA, Dilling DF. The Future of Lung Transplantation [J]. Chest, 2019, 155(3): 465-473. DOI:10.1016/j.chest.2018.08.1036.
[6] Taichman DB, Leopold JA, Elliott G. Continued Progress in Therapy for Pulmonary Arterial Hypertension [J]. N Engl J Med, 2023, 388(16): 1524-1526. DOI:10.1056/NEJMe2300324.
[7] Wang Z, Zhang YX, Shi JZ, et al. RNA m6A methylation and regulatory proteins in pulmonary arterial hypertension [J]. Hypertens Res, 2024, 47(5): 1273-1287. DOI:10.1038/s41440-024-01607-9.
[8] Lasman L, Krupalnik V, Viukov S, et al. Context-dependent functional compensation between Ythdf m(6)A reader proteins [J]. Genes Dev, 2020, 34(19-20): 1373-1391. DOI:10.1101/gad.340695.120.
[9] Zhang Y, Diao HT, Leng MY, et al. YTHDF3-mediated FLCN/cPLA2 axis improves cardiac fibrosis via suppressing lysosomal function [J]. Acta Pharmacol Sin, 2025. DOI:10.1038/s41401-024-01425-2.
[10]Li Y, Wei X, Xiao R, et al. SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy [J]. Circ Res, 2024, 135(1): 93-109. DOI:10.1161/circresaha.124.323698.
[11]de Raaf MA, Schalij I, Gomez-Arroyo J, et al. SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction [J]. Eur Respir J,2014,44(1):160-168. DOI:10.1183/09031936. 00204813.
[12]Beshay S, Sahay S, Humbert M. Evaluation and management of pulmonary arterial hypertension [J]. Respir Med, 2020, 171: 106099. DOI:10.1016/j.rmed.2020.106099.
[13]Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA [J]. Cell Res, 2017, 27(3): 315-328. DOI:10.1038/cr.2017.15.
[14]Zhang H, Guo H, Han F, et al. Regulatory mechanisms of m(6)A methylation in dilated cardiomyopathy [J]. Am J Transl Res, 2025, 17(1): 47-59. DOI:10.62347/aosk8903.
[15]Fang ZM, Zhang SM, Luo H, et al. Methyltransferase-like 3 suppresses phenotypic switching of vascular smooth muscle cells by activating autophagosome formation [J]. Cell Prolif, 2023, 56(4): e13386. DOI:10.1111/cpr.13386.
[16]Kang T, Liu L, Tan F, et al. Inhibition of YTHDF1 prevents hypoxia-induced pulmonary artery smooth muscle cell proliferation by regulating Foxm1 translation in an m6A-dependent manner [J]. Exp Cell Res, 2023, 424(2): 113505. DOI:10.1016/j.yexcr.2023.113505.
[17] Zhang J, Huang WQ, Zhang YR, et al. Upregulation of eIF2α by m(6)A modification accelerates the proliferation of pulmonary artery smooth muscle cells in MCT-induced pulmonary arterial hypertension rats [J]. J Cardiovasc Transl Res, 2024, 17(3): 598-608. DOI:10.1007/s12265-023-10458-7.
[18] Gao XF, Chen AQ, Tang HY, et al. m(6)A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway [J]. Arterioscler Thromb Vasc Biol, 2024, 44(12): 2543-2559. DOI:10.1161/atvbaha.124.321399.
[19]Marinho Y, Villarreal ES, Loya O, et al. Mechanisms of lung endothelial cell injury and survival in pulmonary arterial hypertension [J]. Am J Physiol Lung Cell Mol Physiol, 2024, 327(6): L972-l983. DOI:10.1152/ajplung.00208.2024.
[20]Liu W, Zeng Y, Huang L, et al. RHOJ as a novel mechanosensitive modulator of endothelial inflammation [J]. Biochem Biophys Res Commun, 2023, 670: 36-46. DOI:10.1016/j.bbrc.2023.05.099.
[21]Li K, Zhang D, Zhai S, et al. METTL3-METTL14 complex induces necroptosis and inflammation of vascular smooth muscle cells via promoting N6 methyladenosine mRNA methylation of receptor-interacting protein 3 in abdominal aortic aneurysms [J]. J Cell Commun Signal, 2023, 17(3): 897-914. DOI:10.1007/s12079-023-00737-y.
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