Abstract
Introduction: Pulmonary hypertension (PH)-induced RV failure (PH-RVF), a significant prognostic determinant, is characterized by RV endothelial-to-mesenchymal transition (EndMT) and fibrosis. The regulatory control mechanisms of RV EndMT and fibrosis remain unclear. The action of transcription factor Snai1 in EndMT is proposed to be mediated via LOXL2 recruitment, their nuclear co-translocation and subsequent histone-H3K4 methylation status remodeling. Hypothesis: PH-RVF is associated with EndMT and fibrosis, governed by TGFβ1-Snai1-LOXL2 axis. Targeting Snai1 could serve as a novel therapeutic strategy for PH-RVF. Methods: Male rats received s.c. Monocrotaline (MCT, 60mg/kg, n=7; 30-days) or Sugen (20mg/kg, n=7; 3-wk hypoxia+2-wk normoxia) or PBS (CTRL, n=7). For Snai1-KD, MCT rats received siSnai1 (n=6; 5nM every 3-4d, IV) or scramble (n=7) from day 14-30. Echo and cath were performed. RVs were stained for fibrosis and EndMT. RV RNASeq and PCR validation performed. Human RVs (CTRL n=3; PAH n=7) were stained with trichrome and Snai1/LOXL2. Snai1-KD was performed on human coronary artery endothelial cells (HCAECs) under hypoxia+TGFβ1 (72h). 21 different Histone-H3 modifications were assessed in rat RVs. Values are mean±SD. Results: MCT and SuHx rats had increased RVSP and Fulton Index (FI) and decreased RVFAC (all p <0.001). RNASeq showed EndMT as the top upregulated pathway. RV EndMT, fibrosis and myofibroblast transition were increased in MCT and SuHx rats and PH-RVF patients. RV TGFβ1, Snai1 and LOXL2 were increased in MCT and SuHx. Snai1+LOXL2 colocalized in nucleus in MCT and SuHx rats and human RVs. Snai1-KD showed decreased Snai1 expression (~3-fold), RVSP (45±2 mmHg; p <0.05), FI (0.41±0.01; p <0.05) and increased RVFAC (24±0.01; p<0.05). Snai1-KD resulted in decreased RV LOXL2, EndMT and fibrosis. RNASeq showed EndMT as top downregulated pathway and decreased fibrotic DEGs. Only RV H3K4me2 upregulation was reversed by Snai1-KD. Snai1-KD inhibited hypoxia+TGFβ1-induced EndMT in HCAECs by decreasing Snai1+LOXL2 expression and co-localization. Conclusions: PH-RVF is associated with EndMT, fibrosis and H3K4me2 status remodeling mediated via TGFβ1-Snai1-LOXL2 axis. Targeting Snai1 is a novel therapeutic strategy for PH-RVF.
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