# Histone Deacetylase Inhibition: A Novel Approach to Cardioprotection

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2020 · $409,562

## Abstract

Project Summary: Histone deacetylases (HDACs) have emerged as an important mechanism in regulating
cardiovascular diseases, and this holds promise in developing efficacious and clinical relevant therapeutic
strategies. This is a competitive renewal application to continue our studies of HDAC inhibition, which is critical
to the development of myocardial protection. During the past funding periods, we have well established that
inhibition of HDAC leads to a profound cardioprotection in attenuating myocardial I/R injury and reversing
cardiac remodeling. We have discovered that p38 is subject to regulation by acetylation, and p38 acetylation is
associated with HDAC inhibition-induced cardioprotective effects. We have demonstrated that HDAC inhibition
enhances cardiac repair through stimulating endogenous myoangiogenesis. Non-specific HDAC inhibition is
conceived as a major hurdle to achieving a promising therapeutic implication in the future. Our recent studies
have sought to explore the significance of HDAC isoforms in modulating cardiac pathophysiology. Our
interesting observation indicated that HDAC 4 isoform mainly involves HDAC inhibitors-induced cellular
protection, which was associated with the degradation of HDAC4 protein. p38-regulated/activated kinase
(PRAK), an identified novel and poorly characterized p38 substrate, is crucial to enhancing angiogenesis. Our
latest discovery indicates that genetic inhibition of PRAK eliminated HDAC inhibition-induced cardioprotection
and mitigated angiogenesis. These findings have led us to speculate that inhibition of HDAC4 and subsequent
PRAK activation occurs following HDAC inhibition, leading to protective effects. The proposed studies will test
the central hypothesis that HDAC4 inhibition-mediated PRAK activation induces myocardial protection
and angiogenesis. The specific aims of our proposed studies are the following: Specific Aim 1: Determine the
role of HDAC4 and its ubiquitination in mediating myocyte survival in hypoxia in vitro. Specific Aim 2:
Determine the in vivo role of cardiac-specific HDAC4 and HDAC inhibitor in myocardial ischemia and
angiogenesis. Specific Aim 3: Elucidate HDAC4 deletion or HDAC inhibitor-mediated protection and
angiogenesis via PRAK signaling. Specific Aim 4: Define preclinical perspectives of HDAC inhibitor-mediated
protection is proteasome pathway using a preclinical large animal model. Taken together, the proposed studies
of this competitive renewal application will for the first time establish that HDAC4 associated with PRAK
constitutes a crucial pathway to mediate myocardial injury and angiogenesis. All of these studies will not only
uncover a novel and exciting mechanism in cell signaling and myocardial protection, but will provide the
translational evidence that will have great potential to develop a new therapeutic approach to improve human
health.

## Key facts

- **NIH application ID:** 9704022
- **Project number:** 5R01HL089405-09
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** TING C ZHao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,562
- **Award type:** 5
- **Project period:** 2009-08-14 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9704022

## Citation

> US National Institutes of Health, RePORTER application 9704022, Histone Deacetylase Inhibition: A Novel Approach to Cardioprotection (5R01HL089405-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9704022. Licensed CC0.

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