OTULIN aggravate aneurysm/aortic dissection by promoting vascular smooth muscle cell phenotype switching via the DDX17 -FGF2 Axis

Background Aortic aneurysm/dissection (AAD) is a life-threatening disease lacking effective pharmacological treatment. Protein ubiquitination plays a pivotal role in cardiovascular diseases. However, the possible contribution of the deubiquitinating enzyme OTULIN (OTU deubiquitinase with linear linkage specificity) to AAD pathogenesis remains elusive. Methods Through integrative analysis of RNA-sequencing data from human and mouse AAD tissues with a deubiquitinase database, we identified OTULIN as a key candidate. We generated vascular smooth muscle cell (VSMC)-specific OTULIN knockout mice and established an AAD model using β-aminopropionitrile (BAPN). We employed multiple molecular biological techniques to explore the role of OTULIN in VSMC phenotype switching. Results We found that OTULIN was significantly increased in AAD patients and BAPN-induced AAD mice. VSMC-specific OTULIN knockout ameliorated BAPN-induced AAD, whereas VSMC-specific overexpression by rAAV9-SM22α-OTULIN (recombinant adeno-associated virus serotype 9 expressing Flag-tagged OTULIN under SM22α promoter) aggravated BAPN-induced AAD progression. Mechanistically, we identified DDX17 (DEAD-box helicase 17) as a substrate of OTULIN through interactome analysis. OTULIN removed the linear ubiquitin of DDX17 and promoted its proteasomal degradation. Consequently, Angiotensin II-induced DDX17 downregulation activated FGF2 transcription, leading to VSMC phenotype switching. Conclusions Our findings demonstrate that OTULIN acts as a pathological driver of AAD by destabilizing DDX17 and activating the FGF2 axis. Targeting OTULIN may represent a novel therapeutic strategy for AAD.