ANTXR1 blockade enhances cardiac function in preclinical models of heart failure.

IF 10.8 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Nicola Boccella, GuoJun Yu, Steven Seaman, Yang Feng, Jaewon Lee, Francesco Tomassoni-Ardori, Liping Yang, Kuo-Sheng Hsu, James M Dunleavey, Jodi Becker, Mary Beth Hilton, Karen Morris, Niza Borchin, Daeho So, Pradip Bajgain, Sudhirkumar Yanpallewar, Ryan T Gross, Krish C Dewan, Dawn E Bowles, Darren A Yuen, Lino Tessarollo, Brad St Croix
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引用次数: 0

Abstract

Heart disease, a leading cause of mortality worldwide, is in urgent need of improved therapies. Fibrosis, an accumulation of collagen-rich extracellular matrix in response to injury, is a hallmark of heart disease, but clinical agents that can interfere with the fibrotic pathway do not yet exist. Here we show that ANTXR1/TEM8, a pathology-induced transmembrane protein required for collagen removal, exacerbates injury in multiple models of heart failure. Genetic disruption of Antxr1 and treatment with human neutralizing antibodies prevented heart deterioration following acute myocardial infarction. ANTXR1 pharmacological blockade also improved heart function in models of pressure overload and obesity-induced heart disease with preserved ejection fraction. Improved heart function was accompanied by enhanced exercise tolerance. Mechanistic studies revealed an ANTXR1-antibody-driven improvement in post-infarct scar formation followed by attenuation of late-stage, chronic TGFβ-mediated extracellular matrix remodeling. Thus, ANTXR1-mediated collagen turnover during heart failure is both maladaptive and druggable, providing avenues for therapeutic intervention.

ANTXR1阻断可增强心衰临床前模型的心功能。
心脏病是世界范围内导致死亡的主要原因,迫切需要改进治疗方法。纤维化是一种富含胶原蛋白的细胞外基质对损伤的反应,是心脏病的一个标志,但目前还不存在能够干扰纤维化途径的临床药物。本研究表明,病理诱导的胶原蛋白去除所需的跨膜蛋白ANTXR1/TEM8加重了多种心力衰竭模型的损伤。Antxr1基因破坏和人类中和抗体治疗可防止急性心肌梗死后心脏恶化。ANTXR1药物阻断也改善了压力过载和肥胖引起的射血分数保留的心脏病模型的心脏功能。心脏功能的改善伴随着运动耐受性的增强。机制研究显示,antxr1抗体驱动的梗死后瘢痕形成改善,随后是晚期慢性tgf β介导的细胞外基质重塑的衰减。因此,心衰期间antxr1介导的胶原蛋白转换既不适应又可药物化,为治疗干预提供了途径。
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
CiteScore
5.70
自引率
0.00%
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