Myocardial infarction and tissue ischemia induce cell death, inflammation, and transient mesenchymal transition in endothelial cells (ECs). Here, we show that acute myocardial infarction (AMI) leads to long-term changes in chromatin accessibility, particularly in regions regulating key mediators of endothelial antigen presentation and senescence.
To investigate long-term effects of AMI on endothelial cells, we performed single-nuclei-ATAC sequencing of mice hearts 28 days post-infarction. We found a significant increase in the accessibility of gene loci associated with cardiac inflammation such as Smad3, a key intracellular mediator of Transforming Growth Factor-beta signalling, and Ciita, a positive regulator of the Major Histocompatibility Complex class II (MHCII), important for T-cell activation. Both showed an increased expression in ECs of mice at 28 days after infarction and in single-nuclei sequencing data of patients with ischemic heart failure. To further investigate these gene targets, we utilized in vitro siRNA silencing to explore the functional activity of these genes in ECs. Silencing of CIITA reduced MHCII class gene expression in vitro. Endothelial specific in vivo knockdown of Ciita two weeks post AMI improves heart function in mice compared to control animals. In addition, we found that Zbtb16, a zinc finger and BTB domain containing transcription factor, shows a significant decrease in gene locus accessibility. Reduced expression of Zbtb16 is known to induce cellular senescence and impair endothelial cell function. Indeed, we found an accumulation of senescence cells in the infarct zone by acidic β-galactosidase staining and spatial RNA transcriptomics, which further confirmed the decrease of Zbtb16 in these regions. Endothelial-specific overexpression of Zbtb16 via AAV after myocardial infarction improves heart function over 3 months compared to control. Together, our data suggest that myocardial infarction initiates long-term epigenetic reprogramming that promotes sustained endothelial antigen presentation and senescence.
Understanding how endothelial cells (ECs) respond to myocardial infarction (MI) is critical for improving recovery after heart failure. This study reveals that ECs undergo long-lasting epigenetic changes that promote chronic inflammation and senescence. These persistent alterations may contribute to adverse cardiac remodeling and impaired healing. By identifying key regulators such as CIITA and ZBTB16, this work highlights potential therapeutic targets to modulate EC behaviour after MI. Targeting these pathways could reduce long-term endothelial dysfunction, improve vascular health, and ultimately enhance outcomes in patients with ischemic heart disease.
