Exosomal TIMP4 from myocardial cell relieves heart failure by influencing Th17/Treg Balance.

IF 1.9 4区医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS

Cardiology Pub Date : 2025-05-26 DOI:10.1159/000545905

Dapeng Wu, Chunfeng Li, Hongjie Li, Lei Yu, Wenting Lin

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引用次数: 0

Abstract

Introduction: The progression of heart failure (HF) has been independently linked to both tissue inhibitor of metalloproteinase-4 (TIMP4) and the equilibrium between regulatory T (Treg) as well as T helper 17 (Th17) cells. Despite these associations, the interplay between TIMP4 and the Th17/Treg ratio remains poorly understood. Our research sought to elucidate the impact of TIMP4 on HF pathogenesis, with a particular emphasis on its influence on Th17 and Treg lymphocyte populations.

Methods: Bioinformatics analysis of the GSE196656 dataset was conducted. An isoprenaline-induced Sprague-Dawley rat model of heart failure was used, with rats divided into groups: HF alone, HF with TIMP4 overexpression, and HF with TIMP4 knockdown. Heart failure in primary myocardial cell cultures was induced using Angiotensin II, and exosomes were collected from the culture medium. ELISA, western blot, TUNEL staining, qRT-PCR, RNA extraction analysis the impact of TIMP4 on heart failure. Additionally, purified naïve CD4+ T cells from rats were used in vitro to investigate TIMP4's influence on Th17 and Treg cell differentiation.

Results: Analysis of the GSE196656 dataset revealed significant upregulation of TIMP4 in heart failure. Myocardial exosomal TIMP4 was significantly elevated in the heart failure model. In the experimental rat model, TIMP4 overexpression significantly reduced plasma levels of biomarkers related to heart injury as well as inflammation, enhanced indicators of heart function and suppressed cell death in the heart muscle. Furthermore, TIMP4 overexpression decreased IL-17 levels and the Th17 cell proportion while promoting Treg cell differentiation and increasing IL-10 levels. In vitro studies demonstrated that TIMP4 effectively inhibits the differentiation of Th17 cells and promotes the growth of Treg cells. These effects were observed to vary depending on the dosage.

Conclusion: TIMP4 overexpression exerts a protective effect in heart failure by inhibiting myocardial injury, inflammation, and apoptosis, and by regulating immune cell balance. These findings imply that targeting TIMP4 could potentially serve as a therapeutic strategy for heart failure, as it has the ability to regulate immune responses and minimize damage to the myocardium.

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心肌细胞外泌体TIMP4通过影响Th17/Treg平衡缓解心力衰竭。

心衰（HF）的进展与组织金属蛋白酶-4抑制剂（TIMP4）和调节性T （Treg）和辅助性T 17 （Th17）细胞之间的平衡独立相关。尽管存在这些关联，TIMP4与Th17/Treg比率之间的相互作用仍然知之甚少。我们的研究旨在阐明TIMP4对HF发病机制的影响，特别强调其对Th17和Treg淋巴细胞群的影响。方法：对GSE196656数据集进行生物信息学分析。采用异丙肾上腺素诱导的Sprague-Dawley大鼠心力衰竭模型，将大鼠分为单纯HF组、TIMP4过表达组和TIMP4敲低组。用血管紧张素II诱导原代心肌细胞培养心力衰竭，并从培养基中收集外泌体。ELISA、western blot、TUNEL染色、qRT-PCR、RNA提取分析TIMP4对心力衰竭的影响。此外，利用纯化的naïve大鼠CD4+ T细胞体外研究TIMP4对Th17和Treg细胞分化的影响。结果：对GSE196656数据集的分析显示，TIMP4在心力衰竭中显著上调。心肌外泌体TIMP4在心力衰竭模型中显著升高。在实验大鼠模型中，TIMP4过表达显著降低了与心脏损伤和炎症相关的生物标志物的血浆水平，增强了心功能指标，抑制了心肌细胞死亡。此外，TIMP4过表达降低IL-17水平和Th17细胞比例，促进Treg细胞分化，提高IL-10水平。体外研究表明，TIMP4能有效抑制Th17细胞的分化，促进Treg细胞的生长。据观察，这些效果因剂量而异。结论：TIMP4过表达通过抑制心肌损伤、炎症和凋亡，调节免疫细胞平衡，对心力衰竭具有保护作用。这些发现表明，靶向TIMP4可能作为心力衰竭的治疗策略，因为它具有调节免疫反应和最小化心肌损伤的能力。

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来源期刊

Cardiology 医学-心血管系统

CiteScore

3.40

自引率

5.30%

发文量

审稿时长

1.5 months

期刊介绍： ''Cardiology'' features first reports on original clinical, preclinical and fundamental research as well as ''Novel Insights from Clinical Experience'' and topical comprehensive reviews in selected areas of cardiovascular disease. ''Editorial Comments'' provide a critical but positive evaluation of a recent article. Papers not only describe but offer critical appraisals of new developments in non-invasive and invasive diagnostic methods and in pharmacologic, nutritional and mechanical/surgical therapies. Readers are thus kept informed of current strategies in the prevention, recognition and treatment of heart disease. Special sections in a variety of subspecialty areas reinforce the journal''s value as a complete record of recent progress for all cardiologists, internists, cardiac surgeons, clinical physiologists, pharmacologists and professionals in other areas of medicine interested in current activity in cardiovascular diseases.