USP13 facilitates pressure overload induced vascular remodeling and phenotypic transition of VSMCs via deubiquitinating Beclin-1.

Pressure overload-induced vascular remodeling is a complex physiological response that can result in detrimental cardiovascular diseases. Ubiquitination plays a critical role in this process; however, the role and specific mechanism of deubiquitinating enzyme USP13 in vascular remodeling remain poorly understood. Male C57BL/6J mice were subjected to pressure overload via transverse aortic constriction to investigate USP13's effects in arterial remodeling. Primary vascular smooth muscle cells (VSMCs) were employed to investigate the role of USP13 on VSMC phenotype transition and potential mechanism. Mechanical stretch increased USP13 protein levels in vascular tissues while downregulating Acta2. Similarly, in both rat and human aortic VSMCs, PDGF-BB treatment significantly raised USP13 mRNA and protein levels. Notably, USP13 overexpression worsened arterial wall thickening in TAC mice and decreased Acta2 levels, whereas Spautin-1 treatment had a protective effect. At the cellular level, knocking down USP13 mitigated PDGF-BB-induced VSMC proliferation, as indicated by lower PCNA levels and reduced EdU (+) cell counts. Additionally, USP13 overexpression enhanced VSMC migration, demonstrated by scratch and transwell experiments. USP13 also aggravated PDGF-BB-induced downregulation of ACTA2 and Transgelin while promoting OST elevation. Mechanistically, USP13 interacted with Beclin-1, facilitating its deubiquitination and promoting autophagic flux, as shown by increased LC3 II/I ratios and decreased p62 levels. Moreover, BHLHE40 was explored as a new transcription factor of USP13, and BHLHE40 can regulate VSMCs proliferation and migration by transcriptionally activating USP13. In conclusion, our findings elucidate the role of USP13 in vascular remodeling under pressure overload, suggesting that targeting USP13 may offer therapeutic potential for pathological vascular disorders.