Volume 4 Issue 1
Jan.  2024
Turn off MathJax
Article Contents
Tongzhu Jin, Zhen Ye, Ruonan Fang, Yue Li, Wei Su, Qianqian Wang, Tianyu Li, Hongli Shan, Yanjie Lu, Haihai Liang. Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis[J]. Frigid Zone Medicine, 2024, 4(1): 41-50. doi: 10.2478/fzm-2024-0005
Citation: Tongzhu Jin, Zhen Ye, Ruonan Fang, Yue Li, Wei Su, Qianqian Wang, Tianyu Li, Hongli Shan, Yanjie Lu, Haihai Liang. Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis[J]. Frigid Zone Medicine, 2024, 4(1): 41-50. doi: 10.2478/fzm-2024-0005

Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis

doi: 10.2478/fzm-2024-0005
More Information
  •   Background and Objective  Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance. The Wnt signaling pathway is closely implicated in organ fibrosis, and Notum, a highly conserved secreted inhibitor, modulates Wnt signaling. The objective of this study was to explore the role and mechanism of Notum in cardiac fibrosis.  Methods  A mouse model of cardiac remodeling was established through left coronary artery ligation surgery, with the addition of Notum injection following myocardial infarction surgery. The protective effect of Notum on myocardial infarction was assessed by evaluating cardiac function, including survival rate, echocardiographic assessment, and cardiac contraction analyses. Inflammatory cell necrosis and infiltration were confirmed through H & E and Masson staining. The expression of fibrosis-related genes and β-catenin pathway markers was detected using Western blot quantificational RT-PCR (qRT-PCR). Additionally, EdU, wound healing, and immunofluorescence staining analyses were performed to detect the effect of Notum's in transforming growth factor beta-1 (TGF-β1) induced myofibroblast transformation.  Results  The administration of Notum treatment resulted in enhanced survival rates, improved cardiac function, and decreased necrosis and infiltration of inflammatory cells in mice subjected to left coronary artery ligation. Furthermore, Notum effectively impeded the senescence of cardiac fibroblasts and hindered their pathological transformation into cardiac fibroblasts. Additionally, it significantly reduced collagen production and attenuated the activation of the Wnt/β-catenin pathway. Our preliminary investigations successfully demonstrated the therapeutic potential of Notum in both fibroblasts in vitro and in a mouse model of myocardial infarction-induced cardiac fibrosis in vivo.  Conclusion  Notum inhibition of the Wnt/β-catenin signaling pathway and cardiac fibroblast senescence ultimately hampers the onset of cardiac fibrosis. Our findings suggest that Notum could represent a new therapeutic strategy for the treatment of cardiac fibrosis.

     

  • loading
  • [1]
    Heymans S, Gonzalez A, Pizard A, et al. Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential. Eur J Heart Fail, 2015; 17(8): 764-771. doi: 10.1002/ejhf.312
    [2]
    Claeys M J, Rajagopalan S, Nawrot T S, et al. Climate and environmental triggers of acute myocardial infarction. Eur Heart J, 2017; 38(13): 955-960.
    [3]
    Creemers E E, Pinto Y M. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res, 2011; 89(2): 265-272. doi: 10.1093/cvr/cvq308
    [4]
    de Boer R A, De Keulenaer G, Bauersachs J, et al. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur J Heart Fail, 2019; 21(3): 272-285. doi: 10.1002/ejhf.1406
    [5]
    Shih Y C, Chen C L, Zhang Y, et al. Endoplasmic reticulum protein TXNDC5 augments myocardial fibrosis by facilitating extracellular matrix protein folding and redox-sensitive cardiac fibroblast activation. Circ Res, 2018; 122(2): 1052-1068. doi: 10.1161/CIRCRESAHA.117.312130
    [6]
    Driesen R B, Nagaraju C K, Abi-Char J, et al. Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc Res, 2014; 101(3): 411-22. doi: 10.1093/cvr/cvt338
    [7]
    Yu J, Seldin M M, Fu K, et al. Topological arrangement of cardiac fibroblasts regulates cellular plasticity. Circ Res, 2018; 123(1): 73-85. doi: 10.1161/CIRCRESAHA.118.312589
    [8]
    Travers JG, Kamal FA, Robbins J, et al. Cardiac fibrosis: the fibroblast awakens. Circ Res, 2016; 118(6): 1021-1040. doi: 10.1161/CIRCRESAHA.115.306565
    [9]
    Kong P, Christia P, Frangogiannis N G. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci, 2014; 71(4): 549-574. doi: 10.1007/s00018-013-1349-6
    [10]
    Bernaba B N, Chan J B, Lai C K et al. Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol, 2010; 19(5): 308-311. doi: 10.1016/j.carpath.2009.07.004
    [11]
    Wu H, Tang L X, Wang X M, et al. Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling. Acta Pharmacol Sin, 2023; 44(6): 1149-1160. doi: 10.1038/s41401-022-01025-y
    [12]
    Qian L, Hong J, Zhang Y, et al. Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β-Catenin Pathway in Mice. Cell Physiol Biochem, 2018; 46(6): 2551-2560. doi: 10.1159/000489683
    [13]
    Weber K T, Sun Y, Bhattacharya S K, et al. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol, 2013; 10(1): 15-26. doi: 10.1038/nrcardio.2012.158
    [14]
    Frangogiannis N G. Regulation of the inflammatory response in cardiac repair. Circ Res, 2012; 110(1): 159-173. doi: 10.1161/CIRCRESAHA.111.243162
    [15]
    Pentinmikko N, Iqbal S, Mana M, et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature, 2019; 571(7765): 398-402. doi: 10.1038/s41586-019-1383-0
    [16]
    Blyszczuk P, Berthonneche C, Behnke S, et al. Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133(+) progenitors into F4/80(+) macrophages in experimental autoimmune myocarditis. Cardiovasc Res, 2013; 97(2): 219-229. doi: 10.1093/cvr/cvs317
    [17]
    Porter K E, Turner N A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther, 2009; 123(2): 255-278. doi: 10.1016/j.pharmthera.2009.05.002
    [18]
    Yang D, Fu W, Li L, et al. Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction. Clin Sci (Lond), 2017; 131(24): 2919-2932. doi: 10.1042/CS20171256
    [19]
    Tao H, Yang J J, Shi K H, et al. Wnt signaling pathway in cardiac fibrosis: New insights and directions. Metabolism, 2016; 65(2): 30-40. doi: 10.1016/j.metabol.2015.10.013
    [20]
    Dzialo E, Rudnik M, Koning R I, et al. WNT3a and WNT5a transported by exosomes activate WNT signaling pathways in human cardiac fibroblasts. Int J Mol Sci, 2019; 20(6): 1436. doi: 10.3390/ijms20061436
    [21]
    Duan J, Gherghe C, Liu D, et al. Wnt1/betacatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J, 2012; 31(2): 429-442. doi: 10.1038/emboj.2011.418
    [22]
    Xiang F L, Fang M, Yutzey K E. Loss of beta-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice. Nat Commun, 2017; 8(1): 712. doi: 10.1038/s41467-017-00840-w
    [23]
    Miao J, Liu J, Niu J, et al. Wnt/beta-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction. Aging Cell, 2019; 18(5): e13004. doi: 10.1111/acel.13004
    [24]
    Jeong M H, Kim H J, Pyun J H, et al. Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/beta-catenin signaling. Proc Natl Acad Sci U S A, 2017(8); 114: E1345-E1354.
    [25]
    Kakugawa S, Langton PF, Zebisch M, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature, 2015; 519(7542): 187-192. doi: 10.1038/nature14259
    [26]
    Gerhardt B, Leesman L, Burra K, et al. Notum attenuates Wnt/ β-catenin signaling to promote tracheal cartilage patterning. Dev Biol, 2018; 436(1): 14-27. doi: 10.1016/j.ydbio.2018.02.002
    [27]
    Cai B, Tan X, Zhang Y, et al. Mesenchymal stem cells and cardiomyocytes interplay to prevent myocardial hypertrophy. Stem Cells Transl Med, 2015; 4(12): 1425-1435. doi: 10.5966/sctm.2015-0032
    [28]
    Ma H, Killaars A R, DelRio F W, et al. Myofibroblastic activation of valvular interstitial cells is modulated by spatial variations in matrix elasticity and its organization. Biomaterials, 2017; 131: 131-144. doi: 10.1016/j.biomaterials.2017.03.040
    [29]
    Sapudom J, Rubner S, Martin S, et al. The interplay of fibronectin functionalization and TGF-beta1 presence on fibroblast proliferation, differentiation and migration in 3D matrices. Biomater Sci, 2015; 3(9): 1291-301. doi: 10.1039/C5BM00140D
    [30]
    Nagaraju C K, Robinson E L, Abdesselem M, et al. Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J Am Coll Cardiol, 2019; 73(18): 2267-2282. doi: 10.1016/j.jacc.2019.02.049
    [31]
    Voss A K, Krebs D L, Thomas T. C3G regulates the size of the cerebral cortex neural precursor population. EMBO J, 2006; 25(15): 3652-3663. doi: 10.1038/sj.emboj.7601234
    [32]
    Detienne G, De Haes W, Mergan L, et al. Beyond ROS clearance: Peroxiredoxins in stress signaling and aging. Ageing Res Rev, 2018; 44: 33-48. doi: 10.1016/j.arr.2018.03.005
    [33]
    Gourdie R G, Dimmeler S, Kohl P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov, 2016; 15(9): 620-638. doi: 10.1038/nrd.2016.89
    [34]
    Kologrivova I, Shtatolkina M, Suslova T, et al. Cells of the immune system in cardiac remodeling: main players in resolution of inflammation and repair after myocardial infarction. Front Immunol, 2021; 12: 664457. doi: 10.3389/fimmu.2021.664457
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(6)

    Article Metrics

    Article views (246) PDF downloads(8) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return