https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Institut für Pharmakologie und Klinische Pharmakologie Düsseldorf, Deutschland; 3Clinic for Radiation Therapy and Radiooncology Molecular Radiooncology Duesseldorf, Deutschland
Background: Diabetes is not only linked to poor outcomes following cardiovascular events but is also associated with chronic, low-grade inflammation, potentially driven by cellular senescence. Diabetes accelerates the formation and accumulation of senescent cells, which may trigger persistent inflammation within the diabetic heart. This study investigates whether increased cellular senescence contributes to chronic inflammation in a diabetic context.
Methods: To assess inflammatory responses associated with senescence, we isolated plasma and secretomes of isolated hearts from mice consuming a high-fat diet (HFD) for 10 weeks to induce a prediabetic phenotype, known to enhance p21-driven cellular senescence in the heart. Concentrations of pro-inflammatory cytokines in plasma and secretomes were compared to those of age-matched lean controls and HFD mice treated with a short-term senolytic (Quercetin and Dasatinib) regimen. Additionally, single-cell RNA sequencing (scRNAseq) identified cell-specific senescence and inflammation markers. Finally, we assessed the effects of senescent human cardiac fibroblasts on the migratory phenotype of primary neutrophils in vitro.
Results: Diabetic (HFD) mice showed a significant upregulation of Interleukin (IL)-6—a key pro-inflammatory cytokine—in both plasma and heart secretomes compared to lean controls. Senolytic treatment normalized IL-6 levels, reversing the senescence phenotype in treated animals close to that of lean controls. Circulating immune cell populations, including T cells and NK cells, were normalized in senolytic-treated mice, while cardiac neutrophil levels were significantly reduced. scRNA-seq analysis revealed that in diabetic mice p21 expression was elevated specifically in endothelial cells and fibroblasts. IL-6 expression was only elevated in fibroblasts under diabetic conditions and reduced following senolysis. In vitro experiments confirmed that senescent human cardiac fibroblasts secreted elevated IL-6 levels, promoting enhanced neutrophil migration and activation demonstrated in transwell assays using neutrophils from healthy donors.
Conclusions: Our findings indicate that senescent cardiac fibroblasts are a key source of IL-6, contributing to chronic inflammation in diabetic hearts. Senolytic therapy effectively reduces cellular senescence, normalizes IL-6 levels, and decreases neutrophil infiltration, highlighting its therapeutic potential for managing diabetes-associated chronic inflammation and reducing cardiovascular risks.