Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling.

IF 18 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation research Pub Date : 2026-09-11 Epub Date: 2026-08-05 DOI:10.1161/CIRCRESAHA.125.328171

Changzuan Zhou, Lisheng Fu, Tianyou Yuan, Fangfang Li, Fanhuan Tang, Xiaoyu Wu, Yutong Ye, Longzhe Gao, Chenyang Jin, Qitong Zhang, Liang Xu, Shaowen Liu, Songwen Chen, Jun Li

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引用次数: 0

Abstract

Background: Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential.

Methods: We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics.

Results: The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C⁺ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations.

Conclusions: The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.

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肥大细胞St8sia1是驱动心脏重塑的糖-表观遗传检查点。

背景：致病性免疫-心脏串扰是慢性心力衰竭的不适应重构的基础，但直接针对这一轴的治疗缺乏。糖缀合物对信号转导和细胞外基质完整性至关重要，是一种尚未开发的治疗途径。本研究旨在确定糖缀合物代谢酶在免疫-心脏界面的作用，并评估其翻译潜力。方法：我们对人类和小鼠衰竭心脏的大量和单细胞RNA测序数据进行了综合分析。采用压力过载（主动脉横缩）和缺血再灌注小鼠模型，我们使用了全局和肥大细胞（MC）特异性基因缺失、骨髓嵌合体和药物中和。通过多组学分析，包括RNA-seq， ATAC-seq， CUT&Tag和蛋白质组学，获得了机制见解。结果：在小鼠和人的心肌病理重塑过程中，神经节苷脂GD3合成酶St8sia1被选择性地诱导。mc特异性的或造血性的St8sia1缺失保留了心室功能，减轻了纤维化，并显著减少了横断主动脉收缩和缺血再灌注后中性粒细胞和Ly6C+单核细胞的募集。临床级单克隆抗体R24治疗性中和GD3可改善心功能，减少缺血再灌注后瘢痕形成。在机制上，GD3结合了特定的组蛋白变体，如H2A。Z和H3.3C，从而重编程染色质可及性，激活MCs中的促炎和促纤维化转录程序。因此，GD3抑制抑制了MC脱颗粒，破坏了致病性MC-心肌细胞/成纤维细胞串扰，并保留了修复性巨噬细胞群。结论：mc -限制性St8sia1-GD3轴作为糖表观遗传检查点驱动心脏不适应重构。以该轴为靶点代表了一种可翻译的免疫调节策略，以防止进展为慢性心力衰竭。

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.