# HDAC1 Regulation of Endothelial NO

> **NIH NIH F31** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $13,984

## Abstract

PROJECT SUMMARY
 Excess sodium intake accounts for billions of healthcare dollars every year. In 2010, 1.65 million deaths
from cardiovascular disease were attributed to a high salt diet. Furthermore, sodium intake directly correlates
with kidney function and mortality. A high salt diet causes cardiovascular and renal damage by increasing
oxidative stress and impairing endothelial nitric oxide (NO) signaling. The mechanisms by which a high salt diet
leads to NOS3 uncoupling and increased NADPH oxidase 2 (Nox2) expression and activity remains elusive.
NOS3 uncoupling is characterized by an increase in NOS-dependent reactive oxygen species (ROS) and a
decrease in NOS-dependent NO. The central hypothesis to the proposed studies is that high salt increases
endothelial HDAC1 which uncouples NOS3 via post-translational modification (deacetylation) and increases
Nox2 expression and activity via a transcriptional mechanism. In order to study the role of HDAC1 in NOS3
uncoupling, intra-renal arteries and renal endothelial cells will be isolated from normal and high salt fed rats.
HDAC1 activity as well as HDAC1 dependence of NOS3 uncoupling and NOS3 acetylation will be assessed. We
will generate vascular endothelial HDAC1 knockout (VEHDAC1KO) mice to investigate the necessity of HDAC1
in high salt disrupted NO signaling. The juxtamedullary nephron preparation will be used to assess NO signalling
in small intra-renal arteries. In order to identify which NOS3 lysines are susceptible to HDAC1 deacetylation, we
will utilize NOS3 constructs containing specific lysine (K) to arginine (R) or glutamine (Q) mutations. Cdh5-
CreERT2-Nox2KO mice will be used to assess the role of endothelial Nox2 in high salt disrupted NO signaling
in small intra-renal arteries. We will use VEHDAC1KO mice to elucidate the role of HDAC1 in high salt increased
Nox2 complex expression. ChIP-qPCR will be utilized to assess the effect of HDAC1 on histone modifications at
the promoters of the genes of the Nox2 complex. The long-term goal of this project is to understand the role of
HDAC1 in endothelial NO signaling in order to develop novel therapies for cardiovascular disease.

## Key facts

- **NIH application ID:** 10245088
- **Project number:** 5F31HL149235-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Luke Stewart Dunaway
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $13,984
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-12-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245088

## Citation

> US National Institutes of Health, RePORTER application 10245088, HDAC1 Regulation of Endothelial NO (5F31HL149235-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10245088. Licensed CC0.

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