FBLN7 KO attenuates age-related cardiac fibrosis by promoting TGFBR3/ALK1/Smad1 signaling and inhibiting the profibrotic phenotypes of cardiac fibroblasts.
{"title":"FBLN7 KO attenuates age-related cardiac fibrosis by promoting TGFBR3/ALK1/Smad1 signaling and inhibiting the profibrotic phenotypes of cardiac fibroblasts.","authors":"Xuehui Zheng, Guoqing Yao, Huaitao Yu, Binghui Kong, Yuan Zhao, Yang Hu, Xiangping Ma, Jinghan Hai, Panpan Xu, Yun Ti, Peili Bu","doi":"10.7150/thno.116477","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> Aging induces structural and functional changes in the heart, including left ventricular (LV) hypertrophy, a decline in diastolic function, and even heart failure. Fibulin 7 (FBLN7) is a key mediator of extracellular matrix (ECM) remodeling under pathological conditions. In our study, we aim to explore whether FBLN7 is also involved in the development of age-related cardiac fibrosis and its underlying mechanisms. <b>Methods:</b> We generated naturally aged FBLN7 knockout and wild-type mice (18 months old). Western blot and immunofluorescence assays were employed to investigate the biological function of FBLN7 in senescent cardiac fibroblasts. The interaction between FBLN7 and cell membrane receptors was explored through molecular docking and co-immunoprecipitation techniques. The interaction between FBLN7 and natural products was explored through virtual screening, molecular dynamics simulations and surface plasmon resonance (SPR). <b>Results:</b> Our results demonstrated that the cardioprotective effects observed in aged FBLN7 knockout (KO) mice are mediated by the inhibition of profibrotic phenotypes in senescent cardiac fibroblasts (CFs), which reduces age-related myocardial fibrosis and ultimately improves cardiac diastolic function. The observation that overexpressing FBLN7 in fibroblast-specific protein 1 positive (FSP1<sup>+</sup>) cells of aged mice exacerbates age-related myocardial fibrosis further supports this finding. Mechanistically, we identified that FBLN7 promotes the proliferation, migration, actin remodeling, and collagen production of senescent CFs at least partially by binding to TGFBR3 and reducing its protein levels, thereby inhibiting the activation of the ALK1-Smad1/5/9 pathway. Additionally, we identified a natural product, Ginsenoside Ro, that physically interacts with FBLN7 and validated its antifibrotic activity both in vitro and in vivo. <b>Conclusions:</b> These findings reveal FBLN7 reverses the impaired profibrotic phenotypes of senescent CFs, thereby aggravating age-related cardiac fibrosis. Given that age-related fibrosis is a significant pathological factor in heart failure with preserved ejection fraction (HFpEF), downregulating FBLN7 and/or interfering with its function may represent an effective therapeutic strategy for HFpEF.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8531-8552"},"PeriodicalIF":13.3000,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374634/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.116477","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: Aging induces structural and functional changes in the heart, including left ventricular (LV) hypertrophy, a decline in diastolic function, and even heart failure. Fibulin 7 (FBLN7) is a key mediator of extracellular matrix (ECM) remodeling under pathological conditions. In our study, we aim to explore whether FBLN7 is also involved in the development of age-related cardiac fibrosis and its underlying mechanisms. Methods: We generated naturally aged FBLN7 knockout and wild-type mice (18 months old). Western blot and immunofluorescence assays were employed to investigate the biological function of FBLN7 in senescent cardiac fibroblasts. The interaction between FBLN7 and cell membrane receptors was explored through molecular docking and co-immunoprecipitation techniques. The interaction between FBLN7 and natural products was explored through virtual screening, molecular dynamics simulations and surface plasmon resonance (SPR). Results: Our results demonstrated that the cardioprotective effects observed in aged FBLN7 knockout (KO) mice are mediated by the inhibition of profibrotic phenotypes in senescent cardiac fibroblasts (CFs), which reduces age-related myocardial fibrosis and ultimately improves cardiac diastolic function. The observation that overexpressing FBLN7 in fibroblast-specific protein 1 positive (FSP1+) cells of aged mice exacerbates age-related myocardial fibrosis further supports this finding. Mechanistically, we identified that FBLN7 promotes the proliferation, migration, actin remodeling, and collagen production of senescent CFs at least partially by binding to TGFBR3 and reducing its protein levels, thereby inhibiting the activation of the ALK1-Smad1/5/9 pathway. Additionally, we identified a natural product, Ginsenoside Ro, that physically interacts with FBLN7 and validated its antifibrotic activity both in vitro and in vivo. Conclusions: These findings reveal FBLN7 reverses the impaired profibrotic phenotypes of senescent CFs, thereby aggravating age-related cardiac fibrosis. Given that age-related fibrosis is a significant pathological factor in heart failure with preserved ejection fraction (HFpEF), downregulating FBLN7 and/or interfering with its function may represent an effective therapeutic strategy for HFpEF.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.