# Extracellular redox biology links to metabolic and mitochondrial dysfunction in pulmonary hypertension

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2023 · $69,114

## Abstract

PROJECT SUMMARY/ABSTRACT
 Despite novel treatments, pulmonary hypertension (PH) represents a progressive, highly morbid, and
often fatal condition. Recent studies suggest that metabolic derangements such as the glycolytic switch, ROS
production, and mitochondrial dysfunction play a key role in the pathogenesis of PH. Disruptions of ROS
homeostasis, primarily regulated by the superoxide (SOD) family, have been associated with PH.
Extracellular superoxide dismutase (EC-SOD) is the most prevalent isoform of SOD in the vasculature and has
been previously associated with PH in mouse models. In humans, the R213G EC-SOD SNP leads to a
reduced matrix binding affinity of EC-SOD, leading to low vascular concentration but higher plasma levels and
normal activity. In mice, this SNP has been associated with higher right ventricular pressures at baseline that
worsen with hypoxia. Interestingly, these same mice are protected against PH in the Sugen-hypoxia model.
We hypothesize that the redistribution of R213G variant of EC-SOD due to its reduced binding affinity will have
discrepant effects depending on the model of PH and this effect will be due to distinct model-dependent
activation of AMPK and mitochondrial dysfunction in endothelial cells (PAEC) vs. smooth muscle cells
(PASMC). Preliminary data demonstrated that at baseline, mice with the R213G EC-SOD variant have
significant differences in lung and right ventricular (RV) fatty acid oxidation and electron transport chain activity.
To test the effects of loss of vascular EC-SOD in PH, mice with the R213G EC-SOD SNP will be exposed to
chronic hypoxia or Sugen-hypoxia to develop pulmonary hypertension, confirmed via invasive hemodynamic
and histologic measures (Aim 1). Mitochondrial respiration and ROS production will be measured by high-
resolution respirometry and electron paramagnetic resonance, respectively, in whole lung and RV
homogenates as well as human pulmonary artery endothelial and smooth muscle cells (Aim 2).

## Key facts

- **NIH application ID:** 10750457
- **Project number:** 1F32HL167572-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Daniel Antonio Colon Hidalgo
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $69,114
- **Award type:** 1
- **Project period:** 2023-09-02 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10750457

## Citation

> US National Institutes of Health, RePORTER application 10750457, Extracellular redox biology links to metabolic and mitochondrial dysfunction in pulmonary hypertension (1F32HL167572-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10750457. Licensed CC0.

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