Investigating the molecular mechanisms of right ventricular failure in pulmonary hypertension

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PROJECT SUMMARY This project builds on the scientific premise of understanding the precise molecular mechanisms involved in the development of right ventricular failure (RVF) secondary to pulmonary hypertension (PH). PH-RVF is a significant prognostic determinant of morbidity and mortality in PH and is characterized by remodeling and fibrosis. Despite the importance of RV function in PH, the mechanistic details of RVF secondary to PH remain elusive. Although current therapies targeting pulmonary vasculature do offer some functional improvement for PH patients, yet no approved therapies are available till date that directly target the failing RV. The goal of this project is to highlight specific molecular mechanisms responsible for remodeling and fibrosis in the RV that may be targeted as novel therapeutic strategies for PH-induced RVF. This proposal utilizes state-of-the-art RV bulk-RNA sequencing analysis from two pre-clinical rat models of severe PH highlighting endothelial-to-mesenchymal-transition (EndMT) as the top upregulated pathway and Snai1 (Snail) as a novel network hub promoting the development of EndMT and fibrosis in RVF via Snai1-LOXL2-CTGF axis. This proposal tests the hypothesis that PH-RVF is associated with EndMT and fibrosis governed by Snai1-LOXL2-CTGF axis through chromatin remodeling in the RV. Targeting Snai1 and/or LOXL2 could serve as novel therapeutic strategies for PH-RVF. The proposal has the following aims: Aim 1. Determine the mechanistic role of Snai1-LOXL2-CTGF axis in regulating RV EndMT in PH-RVF in vivo and in vitro. Aim 2. Determine the mechanistic role of Snai1-LOXL2-CTGF axis in regulating RV fibrosis in PH-RVF in vivo and in vitro. Aim 3. Investigate the mechanistic basis of Snai1 and/or LOXL2 knockdown as novel therapeutic strategies for PH-RVF in vivo and in vitro. The proposed studies are significant, since they will highlight the importance of targeting Snai1 and its related network in vivo and in vitro to inhibit EndMT and fibrosis and rescue RVF. The proposed studies are innovative, since they will employ tissue/cell- specific analysis to identify and characterize novel therapeutic targets that are highly regulated by tissue/cell- specific Snai1/LOXL2 knockdown/overexpression in the RVs of rats with PH-induced RVF (in vivo studies) as well as Snai1/LOXL2 knockdown/overexpression in human coronary artery endothelial cells, and human cardiac fibroblasts (in vitro studies). Upon completion, the proposed studies will have identified and addressed the current gap in knowledge in the molecular basis of development of PH-induced RVF. The investigations will yield important insights into the role of Snai1 and its co-partners in RV remodeling in RVF and may lead to development of novel RV-specific therapeutic strategies.