The Ets2 super-enhancer modulates endothelial-mesenchymal transition during cardiac ageing

作者：Zhenglong Guo, Lan Li, Junwei Luo, Wei Xue, Shasha Bian, Yongchang Zhu, Dawei Huo, Wenke Yang, Jing Ma, Yibin Hao, Guanwei Fan, Bingtao Hao, Shixiu Liao · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf242 · 被引用次数：3 · 研究领域：Congenital heart defects research、Angiogenesis and VEGF in Cancer、Cardiac Fibrosis and Remodeling

AIMS: Cardiac ageing is characterized by endothelial dysfunction and associated cardiovascular pathologies, often involving endothelial-to-mesenchymal transition (EndoMT) in cardiac endothelial cells. While the transcription factor Ets2, a member of the Ets family, is known to regulate endothelial cell survival and function, its role in EndoMT and cardiac ageing remains poorly understood. METHODS AND RESULTS: To investigate this, we utilized single-nucleus RNA sequencing (snRNA-Seq) in Ets2-super-enhancer (Ets2-SE)-deficient mice to examine the regulation of Ets2 expression across various cardiac cell types. We assessed the relationship between Ets2 expression and heart ageing and evaluated the characteristics of cardiac ageing in Ets2-SE-deficient mice. Furthermore, we generated endothelial cell-specific Ets2 knockout mice (ECKO) to investigate the role of Ets2 in EndoMT of cardiac endothelial cells both in vitro and in vivo. Our results establish a link between decreased Ets2 expression and the development of ageing-associated cardiac pathological remodelling. Through data analyses, we identified a super-enhancer (Ets2-SE) that regulates Ets2 expression in the heart. Ets2-SE-deficient mice exhibited significantly lower Ets2 expression in cardiac tissues and displayed advanced ageing phenotypes, including increased cardiac fibrosis and dysfunction, compared to wild-type controls. SnRNA-Seq analyses revealed a remarkable downregulation of Ets2 in endothelial cells, correlatin...