STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through regulating F2RL3

Abstract

Rational/ObjectivesPulmonary hypertension (PH) is an incurable disease characterized by pulmonary arterial remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. MethodsPH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. Measurement and Main ResultsThe cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and the TNF- induced PAECs in vitro. In particular, STING significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-{kappa}B axis, which activated the interferon signaling and repressed the BMPR2 signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/ interferon-stimulated genes (ISGs) was observed in vivo. ConclusionsOur findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.