Histone methyltransferase Smyd2 drives vascular aging by its enhancer-dependent activity

Background: Vascular aging is one of the important factors contributing to the pathogenesis of cardiovascular diseases. However, the systematic epigenetic regulatory mechanisms during vascular aging are still unclear. Histone methyltransferase SET and MYND domain-containing protein 2 (Smyd2) is associated with multiple diseases including cancer and inflammatory diseases, but whether it is involved in endothelial cell senescence and aging-related cardiovascular diseases has not been directly proved. Thus, we aim to address the effects of Smyd2 on regulating angiotensin II (Ang II)-induced vascular endothelial cells (VECs) senescence and its epigenetic mechanism. Methods and Results: The regulatory role of Smyd2 in Ang II-induced VECs senescence was confirmed by performing loss and gain function assays. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis was used to systematically screen the potential enhancer during VECs senescence. Here, we found that Smyd2 was significantly upregulated in Ang II-triggered VECs, and deficiency of Smyd2 attenuated senescence-associated phenotypes both in vitro and in vivo. Mechanically, Ang II-induced upregulation of Smyd2 could increase the mono-methylation level of histone 3 lysine 4 (H3K4me1), resulting in a hyper-methylated chromatin state, then further activating enhancers adjacent to key aging-related genes, such as Cdkn1a and Cdkn2a, finally driving the development of vascular aging. Conclusions: Collectively, our study uncovered that Smyd2 drives a hyper-methylated chromatin state via H3K4me1 and actives the enhancer elements adjacent to key senescence genes such as Cdkn1a and Cdkn2a, and further induces the senescence-related phenotypes. Targeting Smyd2 possibly unveiled a novel therapeutic candidate for vascular aging-related diseases.