Research progress of P13K/AKT/KDM5A pathway in atrial fibrillation

doi:10.3760/cma.j.cn441417-20250106-11010

Abstract

Abstract:

Cardiac remodeling is the pathological manifestation in the end stages of diseases such as hypertension, myocardial infarction, and heart failure, with myocardial fibrosis being a core component. Numerous studies have confirmed that atrial remodeling is one of the important mechanisms that trigger atrial fibrillation. Among these, the phosphatidylinositol 3-kinase (PI3K)/Serine/Threonine kinase (Akt) signaling pathway regulates the progression of myocardial fibrosis and is closely related to atrial remodeling. However, research on how lysine-specific demethylase 5A (KDM5A) regulates the occurrence of myocardial fibrosis is still in its early stages. Further investigation into the mechanisms of KDM5A in myocardial fibrosis may become one of the effective strategies for treating atrial fibrillation in the future.

Key words: Myocardial fibrosis, , Atrial fibrillation, , PI3K/AKT, , KDM5A, , Review

摘要：

心脏重构是高血压、心肌梗死、心力衰竭等疾病的终末期病理表现，其核心环节是心肌纤维化。现已有大量研究证实，心房重构是引发心房颤动的重要机制之一。其中，磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase，PI3K）/丝氨酸/苏氨酸激酶（serine/threonine kinase，Akt）信号通路调控心肌纤维化进展，与心房重构密切相关。目前，对于赖氨酸特异性脱甲基酶5 A（lysine-specific demethylase 5A，KDM5A）如何调节心肌纤维化发生的研究处于刚起步阶段，进一步研究KDM5A在心肌纤维化中的作用机制可能成为未来治疗心房颤动的有效策略之一。

关键词: 心肌纤维化, 心房颤动, PI3K/Akt, 赖氨酸特异性脱甲基酶5A, 综述

Zhao Ke, Liu Zhenxing, Shi Dayu, Xu Huipu.

Research progress of P13K/AKT/KDM5A pathway in atrial fibrillation [J]. International Medicine and Health Guidance News, 2025, 31(11): 1812-1815.

赵珂刘振兴时大宇徐会圃.

PI3K/Akt/KDM5A通路在心房颤动中的研究进展 [J]. 国际医药卫生导报, 2025, 31(11): 1812-1815.

References

[1]Lau DH, Linz D, Sanders P. New findings in atrial fibrillation mechanisms[J]. Card Electrophysiol Clin, 2019, 11(4): 563-571. DOI: 10.1016/j.ccep.2019.08.007.

[2]Staerk L, Sherer JA, Ko D, et al. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes[J]. Circ Res, 2017, 120(9): 1501-1517. DOI: 10.1161/CIRCRESAHA.117.309732.

[3]Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS[J]. Eur Heart J, 2016, 37(38): 2893-2962. DOI: 10.1093/eurheartj/ehw210.

[4]Gudbjartsson DF, Holm H, Sulem P, et al. A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation[J]. Eur Heart J, 2017, 38(1): 27-34. DOI: 10.1093/eurheartj/ehw379.

[5]Nattel S. Molecular and cellular mechanisms of atrial fibrosis in atrial fibrillation[J]. JACC Clin Electrophysiol, 2017, 3(5): 425-435. DOI: 10.1016/j.jacep.2017.03.002.

[6]Gourdie RG, Dimmeler S, Kohl P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease[J]. Nat Rev Drug Discov, 2016, 15(9): 620-638. DOI: 10.1038/nrd.2016.89.

[7]Qin W, Cao L, Massey IY. Role of PI3K/Akt signaling pathway in cardiac fibrosis[J]. Mol Cell Biochem, 2021, 476(11): 4045-4059. DOI: 10.1007/s11010-021-04219-w.

[8]Moore-Morris T, Cattaneo P, Puceat M, et al. Origins of cardiac fibroblasts[J]. J Mol Cell Cardiol, 2016, 91: 1-5. DOI: 10.1016/j.yjmcc.2015.12.031.

[9]Lajiness JD, Conway SJ. The dynamic role of cardiac fibroblasts in development and disease[J]. J Cardiovasc Transl Res, 2012, 5(6): 739-748. DOI: 10.1007/s12265-012-9394-3.

[10]Krenning G, Zeisberg EM, Kalluri R. The origin of fibroblasts and mechanism of cardiac fibrosis[J]. J Cell Physiol, 2010, 225(3):631-637. DOI: 10.1002/jcp.22322.

[11]Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis[J]. J Clin Invest, 2017, 127(10): 3770-3783. DOI: 10.1172/JCI94753.

[12]Meng Q, Bhandary B, Bhuiyan MS, et al. Myofibroblast-specific TGFβ receptor II signaling in the fibrotic response to cardiac myosin binding protein C-induced cardiomyopathy[J]. Circ Res, 2018, 123(12): 1285-1297. DOI: 10.1161/CIRCRESAHA.118.313089.

[13]Vasquez C, Morley GE. The origin and arrhythmogenic potential of fibroblasts in cardiac disease[J]. J Cardiovasc Transl Res, 2012, 5(6): 760-767. DOI: 10.1007/s12265-012-9408-1.

[14]Askar SF, Bingen BO, Schalij MJ, et al. Similar arrhythmicity in hypertrophic and fibrotic cardiac cultures caused by distinct substrate-specific mechanisms[J]. Cardiovasc Res, 2013, 97(1):171-181. DOI: 10.1093/cvr/cvs290.

[15]闫景顺,朱林平,张红霞,等.中医药调控心肌纤维化相关信号通路研究进展[J].中国实验方剂学杂志,2024,30(13):230-239. DOI:10.13422/j.cnki.syfjx.20240603.

[16]Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at ser-2448 is mediated by p70S6 kinase[J]. J Biol Chem, 2005, 280(27): 25485-25490. DOI: 10.1074/jbc.M501707200.

[17]Sekulić A, Hudson CC, Homme JL, et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells[J]. Cancer Res, 2000, 60(13): 3504-3513.

[18]Shi B, Ma M, Zheng Y, et al. mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury[J]. J Cell Physiol, 2019, 234(8): 12562-12568. DOI: 10.1002/jcp.28125.

[19]Baretić D, Williams RL. The structural basis for mTOR function[J]. Semin Cell Dev Biol, 2014, 36:91-101. DOI: 10.1016/j.semcdb.2014.09.024.

[20]Huang W, Zhou P, Zou X, et al. Emodin ameliorates myocardial fibrosis in mice by inactivating the ROS/PI3K/Akt/mTOR axis[J]. Clin Exp Hypertens, 2024, 46(1): 2326022. DOI: 10.1080/10641963.2024.2326022.

[21]Kajstura J, Urbanek K, Perl S, et al. Cardiomyogenesis in the adult human heart[J]. Circ Res, 2010, 107(2): 305-315. DOI: 10.1161/CIRCRESAHA.110.223024.

[22]McNab TC, Tseng YT, Stabila JP, et al. Liganded and unliganded steroid receptor modulation of beta 1 adrenergic receptor gene transcription[J]. Pediatr Res, 2001, 50(5): 575-580. DOI: 10.1203/00006450-200111000-00007.

[23]Wadhawan R, Tseng YT, Stabila J, et al. Regulation of cardiac beta 1-adrenergic receptor transcription during the developmental transition[J]. Am J Physiol Heart Circ Physiol, 2003, 284(6): H2146-H2152. DOI: 10.1152/ajpheart.00929.2002.

[24]Takahashi-Yanaga F. Roles of glycogen synthase kinase-3 (GSK-3) in cardiac development and heart disease[J]. J UOEH, 2018, 40(2): 147-156. DOI: 10.7888/juoeh.40.147.

[25]Hailiwu R, Zeng H, Zhan M, et al. Salvianolic acid a diminishes LDHA-driven aerobic glycolysis to restrain myofibroblasts activation and cardiac fibrosis via blocking Akt/GSK-3β/HIF-1α axis[J]. Phytother Res, 2023, 37(10): 4540-4556. DOI: 10.1002/ptr.7925.

[26]Xin Z, Ma Z, Hu W, et al. FOXO1/3: Potential suppressors of fibrosis[J]. Ageing Res Rev, 2018, 41:42-52. DOI: 10.1016/j.arr.2017.11.002.

[27]Ricke-Hoch M, Bultmann I, Stapel B, et al. Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress[J]. Cardiovasc Res, 2014, 101(4): 587-596. DOI: 10.1093/cvr/cvu010.

[28]Pramod S, Shivakumar K. Mechanisms in cardiac fibroblast growth: an obligate role for skp2 and FOXO3a in ERK1/2 MAPK-dependent regulation of p27kip1[J]. Am J Physiol Heart Circ Physiol, 2014, 306(6): H844-H855. DOI: 10.1152/ajpheart.00933.2013.

[29]Li CY, Wang W, Leung CH, et al. KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges[J]. Mol Cancer, 2024, 23(1): 109. DOI: 10.1186/s12943-024-02011-0.

[30]Spangle JM, Dreijerink KM, Groner AC, et al. PI3K/AKT signaling regulates H3K4 methylation in breast cancer[J]. Cell Rep, 2016, 15(12): 2692-2704. DOI: 10.1016/j.celrep.2016.05.046.

[31]Horton JR, Engstrom A, Zoeller EL, et al. Characterization of a linked jumonji domain of the KDM5/JARID1 family of histone h3 lysine 4 demethylases[J]. J Biol Chem, 2016, 291(6): 2631-2646. DOI: 10.1074/jbc.M115.698449.

[32]Blair LP, Cao J, Zou MR, et al. Epigenetic regulation by lysine demethylase 5 (KDM5) enzymes in cancer[J]. Cancers (Basel), 2011, 3(1): 1383-1404. DOI: 10.3390/cancers3011383.

[33]Paolicchi E, Crea F, Farrar WL, et al. Histone lysine demethylases in breast cancer[J]. Crit Rev Oncol Hematol, 2013, 86(2): 97-103. DOI: 10.1016/j.critrevonc.2012.11.008.

[34]Guo L, Guo YY, Li BY, et al. Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting wnt/β-catenin signaling[J]. J Biol Chem, 2019, 294(24): 9642-9654. DOI: 10.1074/jbc.RA119.008419.

[35]Yang X, Bam M, Becker W, et al. Long noncoding RNA AW112010 promotes the differentiation of inflammatory T cells by suppressing IL-10 expression through histone demethylation[J]. J Immunol, 2020, 205(4):987-993. DOI: 10.4049/jimmunol.2000330.

[36]Li QM, Li JL, Feng ZH, et al. Effect of histone demethylase KDM5A on the odontogenic differentiation of human dental pulp cells[J]. Bioengineered, 2020, 11(1): 449-462. DOI: 10.1080/21655979.2020.1743536.

[37]Zhang X, Wang W, Wang Y, et al. Extracellular vesicle-encapsulated miR-29b-3p released from bone marrow-derived mesenchymal stem cells underpins osteogenic differentiation[J]. Front Cell Dev Biol, 2021, 8: 581545. DOI: 10.3389/fcell.2020.581545.

[38]Kong SY, Kim W, Lee HR, et al. The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells[J]. FASEB J, 2018, 32(2): 1108-1119. DOI: 10.1096/fj.201700780R.

[39]Pointon JJ, Harvey D, Karaderi T, et al. The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis[J]. Genes Immun, 2011, 12(5): 395-398. DOI: 10.1038/gene.2011.23.

[40]Kirtana R, Manna S, Patra SK. Molecular mechanisms of KDM5A in cellular functions: facets during development and disease[J]. Exp Cell Res, 2020, 396(2): 112314. DOI: 10.1016/j.yexcr.2020.112314.

[41]Pointon JJ, Harvey D, Karaderi T, et al. The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis[J]. Genes Immun, 2011, 12(5): 395-398. DOI: 10.1038/gene.2011.23.

[42]Heuser M, Yun H, Thol F. Epigenetics in myelodysplastic syndromes[J]. Semin Cancer Biol, 2018, 51:170-179. DOI: 10.1016/j.semcancer.2017.07.009.

[43]魏婷,亓先杰,张旭,等.基于ChIP-seq技术分析心肌成纤维细胞中KDM5A调控的下游靶基因网络[J].中华全科医学,2023,21(9):1474-1477. DOI:10.16766/j.cnki.issn.1674-4152.003149.

[44]张旭.基于转录组学研究AngⅡ/PI3K/Akt/KDM5A通路在心脏纤维化中的作用[D].蚌埠医学院,2023.DOI:10.26925/d.cnki.gbbyc.2023.000063.