Abstract 15069: The Rna M 6 A Demethylase, Fto, Regulates Vascular Remodeling in the Pathogenesis of Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative pulmonary vascular remodeling and progressive elevation of pulmonary vascular resistance that leads to right heart failure and premature death. RNA modifications such as N6-methyladenosine (m 6 A) has have recently been discovered as essential regulators of gene expression but its function in regulating the development of PAH remain unclear. Hypothesis: Fat mass and obesity-associated protein (FTO), as a major m 6 A eraser, acts as a key regulator of endothelial cell (EC) dysfunction and pulmonary vascular remodeling and, thus, is a novel therapeutic target for PAH. Methods: To determine the FTO expression on the idiopathic PAH (IPAH) patients, we performed Western blotting and immunofluorescence on lung tissue from IPAH patients. A novel mouse model with Tie2-Cre-mediated deletion of Fto in endothelial cells was generated and treated with hypoxia for 3 weeks to induce experimental PAH. Measurement of right ventricular systolic pressure (RVSP) and weight ratio of right ventricular versus left ventricular plus septum (RV/LV+S), an indicator of RV hypertrophy were determined. To evaluate the translational potential of targeting FTO in PAH, rats were exposed to monocrotaline to induce pulmonary hypertension and then were treated with FTO inhibitor FB23-2. RVSP, RV/(LV+S) ratio and histology assessment were measured subsequently. Results: FTO expression level is markedly elevated in the endothelial cells of IPAH patients. The Tie2-Cre-Fto (CKO) mice exhibited inhibited PAH under hypoxia treatment as evident by reduced RVSP and lower RV/(LV+S) ratio. Histological and immunofluorescent staining showed that media layer of pulmonary arteries had less cell proliferation and reduced pulmonary vascular remodeling. Moreover, preclinical MCT-rat PAH model showed attenuated PAH phenotype as well as pulmonary vascular remodeling with pharmacological inhibition of FTO. Conclusions: These studies demonstrate that FTO expression markedly elevates in the EC of IPAH patients. Tie2-Cre mediated loss of FTO protects mice from hypoxia-induced PAH. Thus, targeting FTO is a promising therapeutic strategy for PAH.