# Mechanisms of myeloperoxidase and Nox4 interactions in abdominal aortic aneurysm

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2020 · $526,697

## Abstract

PROJECT SUMMARY
Abdominal aortic aneurysm (AAA) disease is a frequent cause of morbidity and mortality.
Roughly 25,000 AAA repairs are performed each year, and AAAs account for over 13,000 deaths
annually in the United States. The underlying mechanisms of AAA formation are unknown, which has
hampered development of effective medical therapies. Here, we focus on the novel hypothesis that
myeloperoxidase (MPO), a leukocyte enzyme expressed primarily in neutrophils (PMNs) that utilizes
H2O2 to promote oxidative stress and inflammation, plays a key role in the pathogenesis of AAA. We
provide novel preliminary data showing that MPO accrues in the aorta during AAA formation, and that
genetic deletion of Nox4, a unique high-output enzymatic producer of H2O2 that is highly expressed in
smooth muscle cells (SMCs), blocks MPO uptake and prevents AAA. We further propose that PMN
activation/MPO accrual in AAA are regulated by prostaglandin D2 (PGD2) and nicotinic acid (GPR109A)
receptors, and that “repurposing” available drugs that target these inflammatory cell receptors is an
attractive therapeutic strategy in AAA. Our central hypothesis is that MPO cooperates with Nox4 to
promote deleterious oxidative stress in AAA, which can be therapeutically modulated by
targeting PGD2 receptors and GPR109A. Three aims are proposed to test our central hypothesis: in
Aim1, we will test the hypothesis that Nox4 cooperates with MPO in the pathogenesis of AAA using
genetically modified mice and a newly developed mass spectrometry assay that will enable us to
determine whether aortic MPO uptake and activity are dependent upon Nox4 during AAA formation.
We will also determine whether overexpression of human MPO in hematopoietic cells enhances AAA
formation, and if so, whether it can be overcome by SMC Nox4 deletion. In Aim 2, we will test the
hypothesis that PGD2 receptors promote PMN/MPO recruitment and MPO-mediated AAA formation
using genetically modified mice in which one or both alleles of DP1 or DP2 have been deleted, coupled
with and pharmacologic DP receptor agonists and antagonists. In Aim 3, we will test the hypothesis
that GPR109A modulates PMN activation and MPO-mediated AAA formation using GPR109A knockout
mice coupled with pharmacologic approaches. A particular emphasis of Aims 2 and 3 is to identify
promising therapeutic strategies that are both feasible and effective for patients with AAA. This
application addresses two significant gaps in the field: i) identifying fundamental mechanisms of AAA
formation and ii) using this knowledge to advance medical treatment for patients with AAA.

## Key facts

- **NIH application ID:** 9924277
- **Project number:** 5R01HL142097-03
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Neal L Weintraub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,697
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924277

## Citation

> US National Institutes of Health, RePORTER application 9924277, Mechanisms of myeloperoxidase and Nox4 interactions in abdominal aortic aneurysm (5R01HL142097-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924277. Licensed CC0.

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