# The role of xanthine oxidoreductase activity and altered metabolism in scleroderma-associated pulmonary arterial hypertension

> **NIH NIH K23** · JOHNS HOPKINS UNIVERSITY · 2022 · $176,580

## Abstract

Project Summary/Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that leads to right
heart failure and death. Patients with scleroderma (SSc) are at high risk for the development of PAH (SSc-PAH),
which is a leading cause of death in SSc. While advances in PAH therapeutics have led to improved outcomes,
survival in SSc-PAH remains dismal, with 57% of patients dying within 5 years of diagnosis. Thus, there is an
urgent need to expand therapeutic options in SSc-PAH, and to identify novel markers of disease risk and severity.
PAH pathogenesis is highly complex, with simultaneous dysregulation of multiple biologic pathways, yet current
therapies for PAH target just three pathways that regulate vasomotor tone. One potentially targetable metabolic
regulator is the protein xanthine oxidoreductase (XOR), which metabolizes purines in an enzymatic reaction that
generates uric acid and reactive oxygen species (ROS). Oxidative injury from over-abundant ROS drives
endothelial cell dysfunction, altered metabolic signaling, and endothelial apoptosis, all early features of PAH
pathobiology. XOR activity increases in experimental PH models, and XOR inhibition with allopurinol prevents
pulmonary hypertensive changes from occurring. XOR activity is increased in PAH patients compared to healthy
controls, and our preliminary data show that serum UA/XOR levels and purine metabolites significantly correlate
with hemodynamics and predict outcomes in SSc-PAH patients. However, XOR has not been studied as a driver
of disease and potential therapeutic target in SSc-PAH.
We hypothesize that increased XOR activity contributes to PAH development in SSc and drives disease
progression through oxidative injury and altered metabolism. By leveraging two rich data sources – the world's
largest known SSc serum biorepository, and an NIH-sponsored prospective cohort of newly diagnosed SSc-PAH
patients - we aim to 1) demonstrate that increased XOR activity and oxidative stress influence development of
PAH in patients with scleroderma, 2) link XOR activity and oxidative stress with phenotypic and outcome data in
SSc-PAH (with a special focus on right ventricular structural and functional phenotypes), and 3) identify metabolic
patterns associated with poor clinical response to currently available PAH therapies. These aims will examine
the role of XOR activity and oxidative stress in SSc-PAH in order to clarify the potential of XOR as a therapeutic
target, and to lay a groundwork for personalized selection of PAH therapies in SSc.

## Key facts

- **NIH application ID:** 10466895
- **Project number:** 5K23HL153781-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Catherine Simpson
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $176,580
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466895

## Citation

> US National Institutes of Health, RePORTER application 10466895, The role of xanthine oxidoreductase activity and altered metabolism in scleroderma-associated pulmonary arterial hypertension (5K23HL153781-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466895. Licensed CC0.

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