Inhibiting the Histone Demethylase Kdm4a Restrains Cardiac Fibrosis After Myocardial Infarction by Promoting Autophagy in Premature Senescent Fibroblasts

Abstract Premature senescent fibroblasts (PSFs) play an important role in regulating the fibrotic process after myocardial infarction (MI), but their effect on cardiac fibrosis remains unknown. Here, the investigation is aimed to determine whether PSFs contribute to cardiac fibrosis and the underlying mechanisms involved. It is observed that premature senescence of fibroblasts is strongly activated in the injured myocardium at 7 days after MI and identified that Kdm4a is located in PSFs by the analysis of scRNA‐seq data and immunostaining staining. Moreover, fibroblast specific gain‐ and loss‐of‐function assays showed that Kdm4a promoted the premature senescence of fibroblasts and cardiac interstitial fibrosis, contributing to cardiac remodeling in the advanced stage after MI, without influencing early cardiac rupture. ChIP‐seq and ChIP‐PCR revealed that Kdm4a deficiency promoted autophagy in PSFs by reducing Trim44 expression through increased levels of the H3K9me3 modification in the Trim44 promoter region. Furthermore, a coculture system revealed that Kdm4a overexpression increased the accumulation of PSFs and the secretion of senescence‐associated secretory phenotype (SASP) factors, subsequently inducing cardiac fibrosis, which could be reversed by Trim44 interference. Kdm4a induces the premature senescence of fibroblasts through Trim44‐mediated autophagy and then facilitates interstitial fibrosis after MI, ultimately resulting in cardiac remodeling, but not affecting ventricular rupture.