# Role of Xanthine Oxidase in Heme-induced Vascular Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $534,408

## Abstract

PROJECT SUMMARY/ABSTRACT
 Vascular injury resulting from hemolysis or ruptured red blood cells is an important clinical issue
associated with numerous hemolytic pathologies including sickle cell disease (SCD), sepsis and iatrogenic
issues in cardiopulmonary bypass surgery, ventricular assist devices and valve replacement. During hemolysis,
red cells release hemoglobin that subsequently discharges heme leading to an oxidative milieu in the
intravascular space. Interestingly, substantial elevation in circulating levels of xanthine oxidase (XO) is also
reported to be associated with numerous hemolytic diseases. While elevated levels of heme are well
characterized in hemolysis pathobiology, the relationship between heme and increased XO activity is unclear.
Here, we provide new data connecting a murine model of intravascular heme injury to excessive amplification in
circulating XO levels (>20-fold). This is important as decades-long bias in the literature would suggest this level
of XO amplification in the circulation to be considered deleterious. Contrary to this long-standing dogma, our new
data suggest XO instead assumes a protective role during heme overload. Pilot studies demonstrate inhibition
of XO with febuxostat during heme overload decreases survival, accelerates organ damage, and elevates
inflammatory responses compared to controls. Consistent with this, plasma from both SCD patients and a murine
model of SCD demonstrate elevation in circulating XO. Importantly, biochemical studies have identified a novel
function for XO: the “splitting” of heme via H2O2 production and subsequent chelation of heme-derived free iron
via uric acid in order to protect the endothelium from overt heme damage. As such, we hypothesize that following
hemopexin saturation, hepatic XO is released to the circulation, binds to endothelium, and assumes a vaso-
protective role during heme overload and SCD-associated heme crisis due to its ability to degrade heme and
subsequently chelate free iron by producing uric acid. We will test this hypothesis using three specific aims:
Aim 1: Define if XO mediates protection during intravascular heme overload. Aim 2: Determine if XO facilitates
“heme splitting” and subsequent iron chelation via XO-derived uric acid. Aim 3: Investigate whether elevated
XO in SCD protects against heme-induced vaso-occlusive crisis. Filling this knowledge gap may uncover new
strategies to address the vascular dysfunction allied to intravascular hemolysis, in general, and SCD, in specific.

## Key facts

- **NIH application ID:** 10400232
- **Project number:** 5R01HL153532-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Eric Eugene Kelley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $534,408
- **Award type:** 5
- **Project period:** 2021-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400232

## Citation

> US National Institutes of Health, RePORTER application 10400232, Role of Xanthine Oxidase in Heme-induced Vascular Dysfunction (5R01HL153532-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400232. Licensed CC0.

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