# Project 2: Scleroderma-Associated Pulmonary Arterial Hypertension: The Role of the Oxidant State

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $260,785

## Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a 
progressive increase in pulmonary vascular resistance that can eventually lead to right ventricular 
failure and death. In systemic sclerosis (SSc), PAH is a leading cause of morbidity and mortality. 
Moreover, patients with SSc-PAH have a poorer prognosis than patients with idiopathic PAH. To 
improve treatment options for SSc-PAH, a better understanding of SSc-PAH pathogenesis is needed. 
Although the exact pathophysiology of PAH is unknown, abnormal cellular metabolism caused by 
altered mitochondrial dynamics, is now considered an important contributor to pathological 
alterations in PAH. During the prior grant period, we demonstrated increased endoplasmic reticulum 
(ER) stress and unfolded protein response (UPR) in circulating immune cells (PBMCs) from SSc 
patients with limited disease (lcSSc), with even higher levels in lcSSc-PAH patients. We also 
demonstrated highly fragmented mitochondria in lcSSc PBMCsM extending these studies to lungs from 
SSc-PAH patients undergoing transplantation, we observed highly increased UPR markers in 
endothelial cells (EC) and macrophages and evidence of increased oxidation. Given the complex 
nature of PAH, a therapeutic agent capable of modulating several key pathways would be an 
attractive addition to the treatment regimen of PAH. As a possible candidate, we have focused on 
dimethyl fumarate (DMF), an agent that augments the intrinsic cellular antioxidant response and was 
recently approved (Tecfidera®) for treatment of multiple sclerosis. Using the rodent-hypoxia model 
of PH, we found DMF prevented and reversed hemodynamic changes, muscularization of pulmonary 
vessels, and right ventricular hypertrophy. DMF also attenuated lung damage caused by oxidative 
stress and reduced immune cell infiltration into lungs of treated mice. To translate these results 
to human SSc-PAH, we propose: 1) Determine the role of altered mitochondrial dynamics on 
activation of immune cells in lcSScM 2) Determine the molecular characteristics of freshly isolated 
PAEC from lcSSc patients with and without PAH undergoing right heart catheterizationM and 3) 
Determine the effect of DMF on the function of distal resistance pulmonary arteries from explanted 
lungs of patients with SSc-PAH undergoing transplantation. These complementary studies will develop 
better understanding of the role of the redox state in the pathogenesis of SSc-PAH, validate 
anti-oxidants, such as DMF, as potential treatment for this entity, and develop collaborative 
disease models between Boston University and the University of Pittsburgh Medical Centers, two 
expert centers with long-standing interest in SSc and SSc-PAH.

## Key facts

- **NIH application ID:** 10022110
- **Project number:** 5P50AR060780-09
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MARIA TROJANOWSKA
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $260,785
- **Award type:** 5
- **Project period:** 2011-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10022110

## Citation

> US National Institutes of Health, RePORTER application 10022110, Project 2: Scleroderma-Associated Pulmonary Arterial Hypertension: The Role of the Oxidant State (5P50AR060780-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10022110. Licensed CC0.

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