产生硫酸软骨素蛋白多糖-4的巨噬细胞会诱发杜氏肌营养不良症的神经-心脏连接损伤。

IF 5.6 2区 医学 Q1 ONCOLOGY
Marika Milan, Fabio Maiullari, Maila Chirivì, Maria Grazia Ceraolo, Rebecca Zigiotto, Andrea Soluri, Silvia Maiullari, Elisa Landoni, Dario Di Silvestre, Francesca Brambilla, Pierluigi Mauri, Veronica De Paolis, Nicole Fratini, Maria Cristina Crosti, Chiara Cordiglieri, Chiara Parisi, Antonella Calogero, Dror Seliktar, Yvan Torrente, Chiara Lanzuolo, Gianpietro Dotti, Mirco Toccafondi, Mauro Bombaci, Elena De Falco, Claudia Bearzi, Roberto Rizzi
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引用次数: 0

摘要

杜兴氏肌营养不良症(DMD)是由于缺乏全形肌营养不良蛋白而引起的,这种蛋白对于维持肌肉细胞(包括心脏和呼吸系统的肌肉细胞)结构的完整性至关重要。尽管在了解与 DMD 相关的分子机制方面取得了进展,但心肌功能不全仍然是导致死亡的主要原因,而现有的治疗策略仍然有限。本研究探讨的假设是,在萎缩性心肌组织中,浸润巨噬细胞(MPs)与神经心肌连接之间的生物通讯存在失调。在 DMD(mdx)小鼠模型中,这种现象受到浸润心脏组织的巨噬细胞过度释放硫酸软骨素蛋白多糖-4(CSPG4)的影响,CSPG4 是神经萌发的关键抑制剂和神经功能调节剂,与扩张型心肌病(DMD 的特征)有关。吉维诺司他是一种组蛋白去乙酰化酶抑制剂,目前正被开发为DMD的临床治疗药物,它能有效恢复mdx小鼠神经-心脏交界处的生理微环境和心脏功能,此外还能减少心脏纤维化、MP介导的炎症和组织中CSPG4的含量。这项研究为了解 DMD 在心脏中的病理生理学提供了新的视角,并确定了潜在的新生物靶点。© 2024 作者。病理学杂志》由 John Wiley & Sons Ltd 代表大不列颠及爱尔兰病理学会出版。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Macrophages producing chondroitin sulfate proteoglycan-4 induce neuro-cardiac junction impairment in Duchenne muscular dystrophy

Macrophages producing chondroitin sulfate proteoglycan-4 induce neuro-cardiac junction impairment in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is caused by the absence of the full form of the dystrophin protein, which is essential for maintaining the structural integrity of muscle cells, including those in the heart and respiratory system. Despite progress in understanding the molecular mechanisms associated with DMD, myocardial insufficiency persists as the primary cause of mortality, and existing therapeutic strategies remain limited. This study investigates the hypothesis that a dysregulation of the biological communication between infiltrating macrophages (MPs) and neurocardiac junctions exists in dystrophic cardiac tissue. In a mouse model of DMD (mdx), this phenomenon is influenced by the over-release of chondroitin sulfate proteoglycan-4 (CSPG4), a key inhibitor of nerve sprouting and a modulator of the neural function, by MPs infiltrating the cardiac tissue and associated with dilated cardiomyopathy, a hallmark of DMD. Givinostat, the histone deacetylase inhibitor under current development as a clinical treatment for DMD, is effective at both restoring a physiological microenvironment at the neuro-cardiac junction and cardiac function in mdx mice in addition to a reduction in cardiac fibrosis, MP-mediated inflammation, and tissue CSPG4 content. This study provides novel insight into the pathophysiology of DMD in the heart, identifying potential new biological targets. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
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