# Perinatal NO signaling in congenital heart disease

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $682,425

## Abstract

Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or
surgical treatment. Children born with congenital heart defects that result in increased PBF develop abnormal
pulmonary vascular reactivity. Although survival for these children has improved they continue to suffer
morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular
disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes
significant morbidity and mortality. Using an experimental lamb model of CHD with increased PBF (Shunt) we
were the first to identify that decreased interactions between heat shock protein 90 (hsp90) and endothelial NO
synthase (eNOS) plays a major role in the reduced nitric oxide (NO) signaling associated with this disease.
Our data implicate decreases in hsp90 activity as well as an increase in eNOS nitration in this process. In
addition, our published data indicate that the loss of hsp90 activity correlates with the disruption of the eNOS
dimeric structure. Based on these data, the overall hypothesis we will test is that eNOS nitration disrupts its
interaction with hsp90 leading to dimer disruption and decreased NO generation. Further, we will investigate if
stimulating hsp90 activity will restore NO signaling and endothelial function. Our investigations will be carried
out in three interrelated, but independent, Aims. We will utilize a translational approach that will integrate
biophysical, cellular and whole animal studies. The successful completion of our studies should yield new
mechanistic insights and will identify new targets that are amenable to therapeutic intervention.

## Key facts

- **NIH application ID:** 9908150
- **Project number:** 5R01HL137282-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Stephen M Black
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $682,425
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908150

## Citation

> US National Institutes of Health, RePORTER application 9908150, Perinatal NO signaling in congenital heart disease (5R01HL137282-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908150. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*