11S Proteasome Activator REGγ Promotes Aortic Dissection by Inhibiting RBM3 (RNA Binding Motif Protein 3) Pathway

Background:Aortic dissection (AD) is a life-threatening cardiovascular disorder with high mortality and lacking underlying mechanisms or effective treatments. REG gamma, the 11S proteasome activator known to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner, emerges as a new regulator in the cardiovascular system. Methods:Using beta-aminopropionitrile (BAPN)-subjected REG gamma knockout AD mice and Ang II (angiotensin II)-treated REG gamma deficiency vascular smooth muscle cells (VSMCs) to explore the effect of REG gamma in AD progression. Results:REG gamma was upregulated in mouse aorta of beta-aminopropionitrile-induced AD model in vivo and Ang II-treated VSMCs in vitro. REG gamma deficiency ameliorated AD progression in beta-aminopropionitrile-induced mice by protecting against the switch in VSMCs from contractile to synthetic phenotype through suppressing RBM3 (RNA-binding motif protein 3) decay. Mechanically, REG gamma interacted with and degraded the RNA-binding protein RBM3 directly, leading to decreased mRNA stability, lowered expression and transcriptional activity of transcription factor SRF (serum response factor), subsequently reduced transcription of VSMCs-specific contractile genes, alpha-SMA (alpha-smooth muscle actin) and SM22 alpha (smooth muscle 22 alpha), caused the switch in VSMCs from contractile to synthetic phenotype and associated AD progression. Ablation of endogenous SRF or RBM3, or overexpressing exogenous RBM3 in VSMCs significantly blocked or reestablished the REG gamma-dependent action on VSMCs phenotypic switch of Ang II stimulation in vitro. Furthermore, exogenously introducing RBM3 improved the switch in VSMCs from contractile to synthetic phenotype and associated AD features caused by REG gamma in vivo. Conclusions:Our results demonstrated that REG gamma promoted the switch in VSMCs from contractile to synthetic phenotype and AD progression by inhibiting RBM3-SRF pathway, indicated that modulating REG gamma-proteasome activity may be a potential therapeutic approach for AD-associated cardiovascular dysfunction.