# Oxidative DNA Damage Regulates Cardiomyocyte Proliferation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $790,429

## Abstract

Project summary
Heart failure is a costly and deadly disease affecting over 5 million Americans. At the core of the
pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In
sharp contrast to the adult heart, our group demonstrated that the newborn mouse heart is capable of
significant regeneration following various types of injury, mediated primarily by proliferation of preexisting
cardiomyocytes. This regenerative capacity is lost by day 7 postnatally, which coincides with cell cycle arrest of
the majority of cardiomyocytes. Our objective is to identify the upstream signals that mediate the switch from
the hyperplastic intrauterine, to the hypertrophic postnatal cardiomyocyte phenotype, and to develop tools to
reverse that process. The relative hyperoxemia of the postnatal environment results in upregulation of
mitochondrial oxidative metabolism and an increased reliance on fatty acid relative to glucose utilization for
energy production. We have demonstrated that these metabolic changes promote an increase in reactive
oxygen species (ROS), oxidative DNA damage, activation of DNA damage response, and cell cycle arrest of
cardiomyocytes. Interestingly, mitochondrial-targeted ROS scavengers prolonged the postnatal window of
cardiomyocyte proliferation and decreased DNA damage, but cell cycle arrest eventually ensued. Our central
hypothesis is that mitochondrial ROS-mediated oxidative DNA damage regulates cardiomyocyte cell cycle in
the postnatal heart. Therefore, in this proposal we aim to examine the mechanism of regulation of
cardiomyocyte cell cycle by DNA damage and the DNA damage response and determine the role of changes
in mitochondrial metabolism in oxidative DNA damage. In addition, we have developed for the first time an
array of ROS detectors that target various nuclear compartments. We will use these novel tools to determine
the spatial distribution of ROS within cardiomyocytes nuclei, and accordingly design targeted nuclear
scavengers to abrogate DNA damage and cell cycle arrest of cardiomyocytes. The long-term goal of this
project is to regenerate the adult heart following injury by re-activating the proliferative capacity of
cardiomyocytes.

## Key facts

- **NIH application ID:** 10148800
- **Project number:** 5R01HL138983-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Hesham Sadek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $790,429
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148800

## Citation

> US National Institutes of Health, RePORTER application 10148800, Oxidative DNA Damage Regulates Cardiomyocyte Proliferation (5R01HL138983-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148800. Licensed CC0.

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