Redox-sensitive enzyme SENP3 mediates vascular remodeling via de-SUMOylation of β-catenin and regulation of its stability

Background: Oxidative stress plays critical pathophysiological roles in vascular remodeling-related cardiovascular diseases, including hypertension, atherosclerosis, and restenosis. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in cancer development and progression. However, the role of SENP3 in vascular remodeling remains unknown. Methods: We generated three mouse models of vascular remodeling due to low shear stress, hypertension, and atherosclerosis. The expression of SENP3 was determined by western blotting and/or immunofluorescence staining in cultured vascular smooth muscle cells (VSMCs), animal models, and human samples. The biological function of SENP3 in proliferation and migration of VSMC and vascular remodeling was further investigated in vitro and in vivo models. Findings: SENP3 was highly expressed in VSMCs of remodeled arteries, accompanied by elevated reactive oxygen species (ROS) levels. In cultured VSMCs, SENP3 protein levels were enhanced by oxidized low-density lipoprotein and Angiotensin II in a ROS-dependent manner. SENP3 overexpression significantly promoted and sh-RNA-mediated knockdown markedly inhibited VSMCs proliferation and migration. Immunofluorescence staining showed that SENP3 expression was correlated with intimal area in remodeled arteries. Furthermore, we demonstrated that SENP3 interacted with beta-catenin and inhibited its proteasome-dependent degradation via de-SUMOylation of beta-catenin. Most importantly, SENP3(+)(/) mice exhibited alleviated vascular remodeling. Interpretation: Our results highlight the important function of SENP3 as a redox sensor and mediator in vascular remodeling. (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

SENP3 is highly expressed in vascular smooth muscle cells during vascular remodeling, promoting cell proliferation and migration through interaction with beta-catenin and inhibition of its degradation, suggesting a crucial role as a redox sensor and mediator in vascular remodeling.