Circulation, Ahead of Print. BACKGROUND:Ischemic heart disease remains a leading cause of mortality worldwide, with adverse remodeling after myocardial infarction driven by inflammation and cardiomyocyte loss.
Although cytotoxic lymphocytes exacerbate myocardial injury and P16 marks cellular senescence in diseased hearts, the cell type–specific functions of P16+populations remain unclear.METHODS:Usingp16-CreER;R26-tdTreporter mice, we mapped P16+cell heterogeneity after myocardial infarction. Senolytic effects were assessed with combined dasatinib and quercetin treatment.
Transcriptomic profiling (bulk and single-cell RNA sequencing) of sorted P16+cells identified secreted factors, validated through in silico predictions and quantitative polymerase chain reaction. Intercellular communication was analyzed using CellChat.
Functional relevance was tested through CCL8 (cytokine [C-C motif] ligand 8) neutralization,Ccl8deletion in P16+cells, lymphocyte depletion, and intersectional genetic ablation of P16+fibroblasts or macrophages using dual-recombinase systems (p16-DreER;Pdgfra-CreER;R26-lr-tdT-DTRandp16-DreER;Cx3cr1-CreER;R26-lr-tdT-DTR).RESULTS:P16 was induced in fibroblasts, macrophages, coronary endothelial cells, and cardiomyocytes after myocardial infarction. Dasatinib and quercetin treatment selectively eliminated P16+macrophages and fibroblasts, improving cardiac function.
Transcriptomic analysis identified P16+fibroblasts and macrophages as the main sources of CCL8. CCL8 blockade reduced infiltration of cytotoxic lymphocytes (CD8+T cells and natural killer cells), decreased cardiomyocyte apoptosis, and enhanced repair.
Circulation published a clinical update in Cardiology on 02 Mar 2026.
The item focuses on P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes.
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