# Investigating the molecular mechanisms of right ventricular failure in pulmonary hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $380,318

## Abstract

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.

## Key facts

- **NIH application ID:** 10691391
- **Project number:** 5R01HL161038-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Soban Umar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $380,318
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691391

## Citation

> US National Institutes of Health, RePORTER application 10691391, Investigating the molecular mechanisms of right ventricular failure in pulmonary hypertension (5R01HL161038-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691391. Licensed CC0.

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