# Pulmonary Hypertension in Genetically Modified Mice

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $746,604

## Abstract

This renewal application builds upon our recent studies indicating that aldehyde dehydrogenase (ALDH)
enzymes can be critical metabolic switches that link chromatin remodeling with gene expression in vascular
and inflammatory cells, and that the dysregulation of specific ALDH isoforms is linked in the pathogenesis of
pulmonary arterial hypertension (PAH). We use pulmonary arterial (PA) endothelial cells (EC), smooth muscle
cells (SMC) and macrophages (MØ) and genetically modified mice to pursue our novel observations. Our
Preliminary Data reveal increased mRNA and protein levels of ALDH1A3 in PA SMC from patients with PAH
versus controls, which is required for their heightened proliferation. The mechanism is related to elevated
nuclear production of acetyl CoA, acetylation of histones at enhancer marks (H3K27ac) and expression of
genes associated with cell cycle progression. In Aim 1, we use RNA Seq and ChIP Seq to probe the
mechanism by which elevated ALDH1A3 increases cell cycle genes as well as other metabolic enzymes, i.e.,
PKM2, DLD and IDH1 and we study the impact of those enzymes on chromatin remodeling and gene
expression. We investigate whether elevated ALDH1A3 could be regulated by mechanisms that are dependent
a well as independent of BMPR2. Further experiments test whether deleting Aldh1a3 in SMC of genetically
modified mice is sufficient to attenuate proliferation of PA SMC and pulmonary hypertension (PH) associated
with chronic hypoxia. In PA EC, we found that a different ALDH isoform ALDH3A1, is increased in response to
laminar flow. In contrast, ALDH2 a mitochondrial enzyme is elevated under static or disturbed flow conditions.
Both ALDH isoforms are expected to preserve PA EC function through multiple metabolic pathways that affect
gene expression. Aim 2 will determine whether ALDH3A1 protects PA EC under laminar flow and ALDH2
under static conditions by relating their metabolomic profile to chromatin accessibility and gene expression.
Localization of these ALDH isoforms will be studied in control and PAH lungs using 3-D vibratome imaging.
Aldh3a1 or Aldh2 will be deleted in EC from genetically modified mice to determine whether this causes more
severe PH following chronic hypoxia or 5-lipoxygenase mediated inflammation. In Aim 3 we focus on
ALDH1A2, an ALDH isoform implicated in polarization of MØ associated with resolution of inflammation, similar
to the reported effect of BMPR2 ligands. We will determine whether deleting Aldh1a2 or Bmpr2 in interstitial
MØ recruited to the lung in association with PH producing conditions, causes more severe disease related to
persistent perivascular inflammation. Proteomics will be applied to analyze the secretome of these Aldh1a2 or
Bmpr2 deleted MØ to better define the nature of the inflammatory response. The impact of the MØ with
Aldh1a2 or Bmpr2 deleted on EC apoptosis or endothelial mesenchymal transition will also be investigated.
Our studies are timely in addressing the significance of ...

## Key facts

- **NIH application ID:** 9853821
- **Project number:** 5R01HL074186-15
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Marlene Rabinovitch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $746,604
- **Award type:** 5
- **Project period:** 2004-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853821

## Citation

> US National Institutes of Health, RePORTER application 9853821, Pulmonary Hypertension in Genetically Modified Mice (5R01HL074186-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853821. Licensed CC0.

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