Exonic CircGUCY1A2 inhibits pulmonary artery smooth muscle cells phenotypic switching via regulating O-glycosylation of COL3A1 in pulmonary hypertension

Pulmonary hypertension (PH) is a fatal disease characterized by pulmonary vascular remodeling, whose regulatory mechanisms remain unclear. Circular RNAs (circRNAs) are a unique class of RNA molecules produced by covalent linkages via back-splicing of linear RNA and play vital roles in regulating physiological and pathological processes. However, the dysregulation of circRNAs and their underlying mechanisms in PH remain unclear. In this study, we identified and investigated the specific functions of circGUCY1A2 in human pulmonary artery smooth muscle cells (PASMCs). We found that circGUYC1A2 expression was markedly downregulated in human PASMCs exposed to hypoxia. Overexpression of circGUCY1A2 impedes the transition of human PASMCs to a synthetic phenotype in vitro and pulmonary vascular remodeling in vivo. Additionally, through mechanistic exploration, we discovered that circGUCY1A2 hindered its glycosylation and attenuated its stability by interacting with the Ser1132 and Ser1145 sites of COL3A1, thereby affecting the expression of Osteopontin (OPN) and inhibiting phenotypic switching in human PASMCs. In conclusion, our study revealed that circGUCY1A2 effectively hindered the transition of human PASMCs to a synthetic phenotype by binding to and regulating the O-glycosylation modification of COL3A1. These results identify circGUCY1A2 as a potential therapeutic target and reveal a novel post-transcriptional regulatory mechanism in PH.

CircGUCY1A2; Collagen type III alpha 1 (COL3A1); O-glycosylation; Phenotypic switching; Pulmonary artery smooth muscle cells (PASMCs); Pulmonary hypertension (PH).