SMC-specific knockdown of circATXN2 significantly alleviated hypoxia-induced pulmonary vascular remodeling and right ventricular dysfunction in a mouse model of pulmonary arterial hypertension.
CircATXN2 promotes hypoxia-induced vascular remodeling via the miR-138-5p/SMURF1 axis, suggesting that targeting this pathway could offer a novel therapeutic strategy for pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a chronic disease that is driven by the abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Although circular RNAs (circRNAs) have been implicated in cardiovascular diseases, their specific roles and mechanisms in pulmonary vascular remodeling remain largely unexplored. The expression of circRNAs was evaluated in lung tissues from PAH mice and hypoxia-treated PASMCs. Gain- and loss-of-function experiments were conducted to assess the effects of circATXN2 on PASMC proliferation and migration in vitro and vascular remodeling in vivo. The levels of circATXN2 and miR-138-5p were detected by qRT-PCR, and the expression of SMAD ubiquitination regulatory factor 1 (SMURF1) was quantified using Western Blot. Interactions among circATXN2, miR-138-5p, and SMURF1 were investigated using bioinformatic prediction, RNA immunoprecipitation, luciferase reporter assays, and functional rescue experiments. We identified that circATXN2, derived from Ataxin-2 (ATXN2), was significantly upregulated both in vivo and in vitro. SMURF1 was increased due to the sequestration of miR-138-5p by circATXN2, which in turn enhanced SMAD 1/5/9 degradation and further interfered with the bone morphogenetic protein (BMP) pathway. Downregulation of circATXN2 significantly decreased the proliferation and migration of PASMCs and suppressed the development of PAH in mice. Furthermore, the pathological processes of circATXN2 could be attenuated either through the miR-138-5p elevation or SMURF1 reduction in PASMCs, proving the existence of circATXN2/miR-138-5p/SMURF1 regulatory axis. Our results demonstrated that circATXN2 promotes hypoxia-induced vascular remodeling via the miR-138-5p/SMURF1 axis, suggesting that targeting this pathway could offer a novel therapeutic strategy for PAH.
Qian et al. (Mon,) conducted a other in Pulmonary arterial hypertension. AAV9-si-circATXN2 (circATXN2 knockdown) vs. AAV9-si-NC (negative control) was evaluated on Right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling. SMC-specific knockdown of circATXN2 significantly alleviated hypoxia-induced pulmonary vascular remodeling and right ventricular dysfunction in a mouse model of pulmonary arterial hypertension.