Abstract 18681: Mir125/tnfaip3/snai2 Axis Promotes Epithelial to Mesenchymal Transition in Group3 Pulmonary Hypertension

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Abstract

Pulmonary fibrosis (PF) is characterized by lung scarring. PF can be sometimes worsened by pulmonary hypertension (PH) known as group3 PH. Here, we have developed a new model of group3 PH in rats which recapitulates human lung pathology and unraveled miR125, via its target Tumor Necrosis Factor Associated Inhibitor Protein 3 (TNFAIP3), leading to Snai2 activation (a transcription factor regulating epithelial to mesenchymal transition), as key molecular mechanisms triggering the transition of PF to PF-PH. RNA were extracted from human (n=3-5) and rats (Wistar, n=6-8). Male rats received tracheal instillation of bleomycin (Bleo, 2.5mg/Kg) at day 0. 2weeks later, rats received a monocrotaline injection (MCT, 60mg/kg, PF-PH) or PBS (PF). Others received tracheal instillation of PBS at day 0, and 2 weeks later MCT (PH) or PBS (CTRL). PH was assessed by direct catheterization and fibrosis was assessed by Ashcroft Score (AS). Values are mean±SEM, p<5% is significant. In rats, lung fibrosis in PF-PH group at the time of MCT injection was 2.9±0.6 and significantly increased to 4.63±0.33 at end of 5 weeks compared to PF (3.63±0.17), CTRL (0.64±0.06) or PH (1.14±0.23). Compared to PF group, PF-PH group had also significantly higher RVSP (52±5 mmHg vs. 32±3, p<5%), and increased pulmonary vascular remodeling (51±0.02 vs. 41±0.02, p<5%). Interestingly, lung miR-125 in PF-PH group was significantly upregulated (4.1±0.8, p<5%) compared to other 3 groups of CTRL (1±0.16), PF (1.08±0.23) and PH (1.05±0.24). TNFAIP3, a predicted target of miR-125, was significantly downregulated in PF-PH group (0.3±0.2, p<5%) vs. CTRL (1±0.16), PF (1.7±0.23) and PH (2.5±0.24). Snai2 expression was increased in PF-PH (2.5±0.81, p<0.05) vs. CTRL (1±0.1), PF (0.41±0.12) or PH (0.37±0.17). Human lung histology showed a significant increase in fibrosis in patients with PF (5.5±0.28) and PF-PH (5.6±0.43) vs. PH (1.8±0.7, p<5%). Vascular remodeling was also increased in patients with PF-PH (51±0.05) and PH (47±0.01) vs. PF (38±0.01, p<5%). Similar to rats, Snai2 expression was also increased 2-fold in PF-PH (2.2±0.63) vs. PF (1±0.08) or PH (1.07±0.1) patients.In conclusion, our animal model recapitulates human pathology and gives evidence of the central role of Snai2 in PFPH.

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