# Cerebral Vascular Redox Regulation in Stroke

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $597,103

## Abstract

Abstract: African Americans (AA) show disparities in ischemic stroke when compared to Euro-Americans, with
2x higher stroke prevalence and mortality, 4x higher incidence of ischemic stroke during middle age, as well as
greater stroke disability, more post-stroke complications, and slower recovery. To reduce stroke morbidity and
mortality and advance therapies to better treat AA with ischemic stroke, an improvement in our understanding of
the basic pathways that regulate oxidative stress damage and cerebral blood flow is needed. Preclinical and
clinical evidence suggest that redox imbalance occurs in ischemic stroke, with increased oxidant formation and
suppressed nitric oxide (NO) signaling, which may be more compromised in the AA population. However, the
mechanisms that contribute to redox imbalance in AA with ischemic stroke remain a major gap in our knowledge.
We have identified that a high frequency variant in cytochrome b5 reductase 3 (CYB5R3) exists in the AA
population (23% minor allele frequency), compared to less than 1% in whites. This CYB5R3 missense variant
confers a threonine to serine amino acid change (T117S) leading to reduced CYB5R3 activity. To test the
importance of this variant in cerebral vascular function following ischemic stroke, we generated a novel CYB5R3
T117S murine model. Preliminary studies show that CYB5R3 T117S mice develop significantly greater infarct
volume, suggesting that CYB5R3 T117S mice are more vulnerable to oxidative stress. Mechanistically, our pilot
studies suggest CYB5R3 T117S serves as a redox regulator of soluble guanylyl cyclase (sGC), the nitric oxide
receptor. Based on these preliminary data, we hypothesize that CYB5R3 T117S causes a redox imbalance by
impairing sGC heme redox regulation leading to exacerbated cerebral blood flow deficiency and ischemic stroke.
Three aims are proposed to test this hypothesis: Aim 1) define whether impaired cerebrovascular function in
Cyb5R3 T117S and SMC Cyb5R3 KO mice causes greater brain infarct and worsened stroke outcomes, Aim
2) determine whether NO-sGC-cGMP-mediated cerebral blood vessel damage causes dysregulation of cerebral
arterial relaxation in Cyb5R3 T117S mice and SMC Cyb5R3 KO mice after ischemic stroke, and Aim
3) determine whether sGC activator and/or sGC stimulator therapy reduces stroke damage in Cyb5R3 T117S
and SMC Cyb5R3 KO mice. Completion of these studies will fill a major gap in our understanding of the role of
CYB5R3 T117S in the pathogenesis of ischemic stroke, potentially developing new precision strategies and
therapies for a large proportion of AA who suffer from ischemic stroke.

## Key facts

- **NIH application ID:** 10883739
- **Project number:** 5R01NS129613-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Adam Carl Straub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $597,103
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883739

## Citation

> US National Institutes of Health, RePORTER application 10883739, Cerebral Vascular Redox Regulation in Stroke (5R01NS129613-02). Retrieved via AI Analytics 2026-08-22 from https://api.ai-analytics.org/grant/nih/10883739. Licensed CC0.

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