Wu Dapeng, Li Chunfeng, Li Hongjie, Yu Lei, Lin Wenting
Ward 1, Department of Cardiovascular Medicine, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China.
Preventive Medicine Teaching and Research Office, School of Public Health, Qiqihar Medical University, Qiqihar, China.
Cardiology. 2025 May 26:1-12. doi: 10.1159/000545905.
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.
Bioinformatics analysis of the GSE196656 dataset was conducted. An isoprenaline-induced Sprague-Dawley rat model of HF was used, with rats divided into groups: HF alone, HF with TIMP4 overexpression, and HF with TIMP4 knockdown. HF in primary myocardial cell cultures was induced using Angiotensin II, and extracellular vesicles were collected from the culture medium. ELISA, Western blot, TUNEL staining, qRT-PCR, and RNA extraction analyzed the impact of TIMP4 on HF. Additionally, purified naïve CD4+ T cells from rats were used in vitro to investigate TIMP4's influence on Th17 and Treg cell differentiation.
Analysis of the GSE196656 dataset revealed significant upregulation of TIMP4 in HF. Myocardial exosomal TIMP4 was significantly elevated in the HF 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.
TIMP4 overexpression exerts a protective effect in HF 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 HF, as it has the ability to regulate immune responses and minimize damage to the myocardium.
心力衰竭（HF）的进展与金属蛋白酶组织抑制剂-4（TIMP4）以及调节性T（Treg）细胞和辅助性T细胞17（Th17）之间的平衡均独立相关。尽管存在这些关联，但TIMP4与Th17/Treg比率之间的相互作用仍知之甚少。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淋巴细胞群体的影响。
对GSE196656数据集进行生物信息学分析。使用异丙肾上腺素诱导的Sprague-Dawley大鼠HF模型，将大鼠分为几组：单纯HF组、TIMP4过表达的HF组和TIMP4敲低的HF组。使用血管紧张素II诱导原代心肌细胞培养中的HF，并从培养基中收集细胞外囊泡。ELISA、蛋白质印迹、TUNEL染色、qRT-PCR和RNA提取分析了TIMP4对HF的影响。此外，使用从大鼠中纯化的初始CD4+T细胞进行体外实验，以研究TIMP4对Th17和Treg细胞分化的影响。
对GSE196656数据集的分析显示HF中TIMP4显著上调。HF模型中心肌外泌体TIMP4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，增强了心脏功能指标并抑制了心肌细胞死亡。此外，TIMP4过表达降低了IL-17水平和Th17细胞比例，同时促进了Treg细胞分化并增加了IL-10水平。体外研究表明，TIMP4有效抑制Th17细胞分化并促进Treg细胞生长。观察到这些作用因剂量而异。
TIMP4过表达通过抑制心肌损伤、炎症和细胞凋亡以及调节免疫细胞平衡，在HF中发挥保护作用。这些发现表明，靶向TIMP4可能作为HF的一种治疗策略，因为它具有调节免疫反应和最小化心肌损伤的能力。
