Abstract 672: SUMOylation of Vps34 by SUMO1 Promotes Phenotypic Switching of Vascular Smooth Muscle Cells by Activating Autophagy in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease without effective therapies. PAH is associated with a progressive increase in pulmonary vascular resistance and irreversible pulmonary vascular remodeling. SUMO1 (small ubiquitin-related modifier 1) can bind to target proteins and lead to protein SUMOylation, an important post-translational modification mechanism with a key role in many diseases. However, the contribution of SUMO1 to PAH remains to be fully characterized. In this study, we explored the role of SUMO1 in the dedifferentiation of vascular smooth muscle cells (VSMCs) involved in hypoxia-induced pulmonary vascular remodeling and PAH. In a mouse model of hypoxic PAH, SUMO1 expression was significantly increased, which was associated with activation of autophagy (increased LC3b and decreased p62), dedifferentiation of VSMCs (reduced α-SMA, SM22 and SM-MHC), and pulmonary vascular remodeling. Overexpression of SUMO1 significantly increased VSMC proliferation, migration, hypoxia-induced VSMC dedifferentiation, and autophagy, but these effects were abolished by inhibition of autophagy by 3-MA. Mechanistically, SUMO1 promotes Vps34 SUMOylation and the assembly of the Beclin-1-Vps34-Atg14 complex, thereby inducing autophagy, whereas Vps34 mutation K840R reduces Vps34 SUMOylation and inhibits VSMC dedifferentiation. In conclusion, our data uncovers an important role of SUMO1 in VSMCs proliferation, migration, activation of autophagy, and phenotypic switching (dedifferentiation) involved in pulmonary vascular remodeling and PAH. Targeting of the SUMO1-Vps34-autophagy signaling axis may be exploited to develop therapeutic strategies to treat PAH.