PRMT1 Upregulates SIRT6 by Enhancing Arginine Methylation of E2F7 to Inhibit Vascular Smooth Muscle Cell Senescence in Aortic Dissection

Abstract

Aortic dissection (AD) is a highly alarming clinical condition of the aorta, with a significant mortality rate. Vascular smooth muscle cell (VSMC) senescence dominantly promotes AD progression. This study planned to clarify the exact functions and mechanisms of protein arginine methyltransferase 1 (PRMT1), E2F7, and Sirtuin 6 (SIRT6) in the VSMC senescence of the AD model. Angiotensin II (Ang II) and β-Aminopropionitrile (BAPN) were used to treat VSMCs or C57BL/6J mice to establish the AD in vitro or in vivo model. Protein expressions were examined by western blot, IHC, and IF staining. Histological change or cell senescence was monitored using H&E or senescence-associated-β-galactosidase (SA-β-gal) staining. Enzyme-Linked Immunosorbent Assay (ELISA) assays were utilized to evaluate senescence-associated secretory phenotype markers' levels. The binding interactions between E2F7 and SIRT6 or PRMT1 and E2F7 were verified by the luciferase reporter, ChIP Co-IP, and GST-pull-down analysis. The ubiquitination levels of E2F7 were assessed using ubiquitination assays. PRMT1, E2F7, and SIRT6 protein levels were decreased in the Ang II-treated VSMCs of the AD model. Moreover, E2F7 repressed cell senescence by transcriptionally regulating SIRT6 in the AD model. PRMT1 silencing promoted cell senescence of VSMCs under Ang II. Further, PRMT1-mediated arginine methylation could maintain the protein stability of E2F7. PRMT1 restrained cell senescence of VSMCs via the E2F7/SIRT6 axis in the AD model. PRMT1 enhanced arginine methylation of E2F7, leading to the upregulation of SIRT6, thereby inhibiting the senescence of VSMCs in the AD model.