FBLN7 KO attenuates age-related cardiac fibrosis by promoting TGFBR3/ALK1/Smad1 signaling and inhibiting the profibrotic phenotypes of cardiac fibroblasts.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-07-28 eCollection Date: 2025-01-01 DOI:10.7150/thno.116477
Xuehui Zheng, Guoqing Yao, Huaitao Yu, Binghui Kong, Yuan Zhao, Yang Hu, Xiangping Ma, Jinghan Hai, Panpan Xu, Yun Ti, Peili Bu
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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.

FBLN7 KO通过促进TGFBR3/ALK1/Smad1信号传导和抑制心脏成纤维细胞的纤维化表型来减轻年龄相关的心脏纤维化。
理由:衰老会引起心脏结构和功能的改变,包括左心室肥厚、舒张功能下降,甚至心衰。纤维蛋白7 (FBLN7)是病理条件下细胞外基质(ECM)重塑的关键介质。在我们的研究中,我们的目的是探索FBLN7是否也参与年龄相关的心脏纤维化的发展及其潜在机制。方法:制备自然衰老FBLN7敲除小鼠和野生型小鼠(18月龄)。采用Western blot和免疫荧光法研究FBLN7在衰老心肌成纤维细胞中的生物学功能。通过分子对接和共免疫沉淀技术探索FBLN7与细胞膜受体的相互作用。通过虚拟筛选、分子动力学模拟和表面等离子体共振(SPR)研究了FBLN7与天然产物的相互作用。结果:我们的研究结果表明,在FBLN7基因敲除(KO)的老年小鼠中观察到的心脏保护作用是通过抑制衰老的心脏成纤维细胞(CFs)的纤维化表型来介导的,从而减少与年龄相关的心肌纤维化,最终改善心脏舒张功能。在老年小鼠的成纤维细胞特异性蛋白1阳性(FSP1+)细胞中过度表达FBLN7会加剧与年龄相关的心肌纤维化,这进一步支持了这一发现。在机制上,我们发现FBLN7通过与TGFBR3结合并降低其蛋白水平,从而抑制ALK1-Smad1/5/9通路的激活,至少部分地促进了衰老CFs的增殖、迁移、肌动蛋白重塑和胶原蛋白的产生。此外,我们发现了一种天然产物,人参皂苷Ro,与FBLN7物理相互作用,并在体外和体内验证了其抗纤维化活性。结论:这些发现表明FBLN7逆转了衰老CFs受损的纤维化表型,从而加重了年龄相关的心脏纤维化。鉴于年龄相关性纤维化是保留射血分数(HFpEF)心力衰竭的重要病理因素,下调FBLN7和/或干扰其功能可能是HFpEF的有效治疗策略。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
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.
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