Exosomal TIMP4 from Myocardial Cell Relieves Heart Failure by Influencing Th17/Treg Balance

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.