A Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts.

IF 16.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation research Pub Date : 2025-01-03 Epub Date: 2024-12-04 DOI:10.1161/CIRCRESAHA.124.325017

Shota Yoshida, Hiroki Hayashi, Takuro Kawahara, Shunsuke Katsuki, Mitsukuni Kimura, Rissei Hino, Jiao Sun, Ryo Nakamaru, Akiko Tenma, Masayoshi Toyoura, Satoshi Baba, Munehisa Shimamura, Tomohiro Katsuya, Ryuichi Morishita, Hiromi Rakugi, Tetsuya Matoba, Hironori Nakagami

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引用次数: 0

Abstract

Background: Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis.

Methods: We coadministered a FAP peptide vaccine with a cytosine-phosphate-guanine (CpG) K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues.

Results: We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P=4.59×10^-3) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm²; FAP vaccine versus angiotensin II and phenylephrine control; P=6.67×10^-3). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models.

Conclusions: Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.

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抗成纤维细胞活化蛋白疫苗通过防止肌成纤维细胞积聚改善小鼠心脏纤维化

背景：肌成纤维细胞是参与慢性反应性心脏纤维化的原代细胞。成纤维细胞活化蛋白（FAP）是一种相对特异性的肌成纤维细胞活化标志物，也是一种潜在的靶分子。本研究旨在阐明靶向FAP的疫苗是否能够消除慢性心脏应激模型小鼠的肌成纤维细胞并减少心脏纤维化。方法：将FAP肽疫苗与CpG K3寡核苷酸佐剂共同接种于雄性C57/BL6J小鼠，证实其抗FAP抗体滴度升高。连续给予血管紧张素II和苯肾上腺素28天后，我们评估心脏纤维化程度和心脏组织中肌成纤维细胞的数量。结果：我们发现，与血管紧张素II和苯肾上腺素对照小鼠相比，接种fap的小鼠心脏纤维化明显减少(3.45±1.11%比8.62±4.79%；P=4.59×10-3)， FAP免疫组化染色显示，FAP阳性细胞的积累也显著减少(4077±1746 vs 7327±1741细胞/mm2；FAP疫苗与血管紧张素II和苯肾上腺素对照的比较P = 6.67×三分)。未观察到由FAP疫苗诱导的抗体依赖性细胞毒性引起的全身性或器官特异性炎症。尽管在组织修复过程中，肌成纤维细胞的短暂激活在维持结构稳健性方面起着重要作用，但FAP疫苗在心肌梗死和皮肤损伤模型中未显示出不良反应。结论：我们的研究表明FAP疫苗可以作为心脏纤维化的一种治疗工具。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.