Notum protects against myocardial infarction-induced heart dysfunction by alleviating cardiac fibrosis
Tongzhu Jin1
Zhen Ye2
Ruonan Fang1
Yue Li1
Wei Su1
Qianqian Wang1
Tianyu Li1
Hongli Shan3
Yanjie Lu3
Haihai Liang3
1.Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD),Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin 150081,China2.Department of Pharmacy,Suqian First Hospital,Suqian 223800,China3.Laboratory of Frigid Zone Cardiovascular Diseases(SKLFZCD),Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin 150081,China;Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin 150081,China
摘要：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.
机标关键词：fibrosisheartagainstalleviatingcardiacdysfunctioninducedinfarction
论文发表日期：2024-01-30
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：10( 41-50 )
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