# Regulatory Role of HDAC in Post-MI Ventricular Remodeling

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2021 · —

## Abstract

Heart disease is the leading cause of death for both men and women with over 600,000 deaths/year
(25% of mortality). Coronary heart disease is the most common type of heart disease with about
715,000 patients suffering a heart attack each year. Death rates in our patient population in the
southeast are even higher with African Americans having higher rates yet. Our VA patients reflect our
local population with elevated risk of heart disease often presenting with hypertension, diabetes,
obesity or overweight, smoking and excessive alcohol use. VA patients who have incurred LV injury
due to myocardial infarction (MI) undergo ventricular remodeling, which can lead to chamber dilation
and progression to congestive heart failure. Monocyte-derived macrophages are believed to play a
major role in the regulation of infarct healing. Post-MI repair is made up of a biphasic process with
phase I mediated by inflammatory M1 macrophages that are phagocytic, and secrete high levels of
MMPs and proinflammatory mediators. By contrast the M2 macrophages produce anti-inflammatory
cytokines and communicate with myofibroblasts, endothelial cells, parenchymal and local progenitor
cells to help coordinate remodeling and repair of the damaged tissue. The controlled recruitment of the
inflammatory monocytes and resulting macrophages is essential for proper healing, but excessive or
prolonged recruitment of these inflammatory monocytes and M1 macrophage results in deleterious
remodeling and heart failure. Histone deacetylases (HDACs) and histone acetyl-transferases (HATs)
are critical players in regulating gene expression via modulation of chromatin structure and the
acetylation of transcription factors. We and others have demonstrated that HDAC inhibition is
efficacious in pre-clinical models of ischemic heart disease. Our data show HDAC inhibition in a model
of MI results in the dramatic increase in the recruitment of reparative macrophages by 1 d post-MI
which correlates with significantly lower LV dilation and preserves LV ejection fraction. Therefore, we
hypothesize that HDACs serve as a master regulator of macrophage polarization, promoting
resolution of inflammation and protection of adverse remodeling through secretion of pro-
reparative factors. By bringing the HDAC activity in the injured myocardium back into balance, we
change the kinetics of appearance of reparative macrophages via epigenetic regulation of
macrophages and favorably influence the complex cross-talk between macrophages and neutrophils
and macrophages and fibroblasts. We have 3 Aims to test our hypothesis. Aim 1 Determine how HDAC
inhibition in the post MI ventricle affects macrophage phenotype, function and resulting tissue
microenvironment in order to foster infarct healing. Aim 2 Determine how nanoparticle targeted delivery
of HDAC inhibition to monocytes and macrophages affects the post-MI macrophage transcriptome,
function and resulting tissue microenvironment. Aim 3 Determine how nanopartic...

## Key facts

- **NIH application ID:** 10265359
- **Project number:** 5I01BX002327-07
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Donald R. Menick
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265359

## Citation

> US National Institutes of Health, RePORTER application 10265359, Regulatory Role of HDAC in Post-MI Ventricular Remodeling (5I01BX002327-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10265359. Licensed CC0.

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