Regulation of mammalian cardiomyocyte cell cycle has been a central question in cardiovascular biology for decades, secondary to the burden of heart failure. Although the adult heart does not have a significant regenerative potential, it has recently become clear that measurable cardiomyocyte turnover does in fact occur in the adult heart, mediated by proliferation of pre-existing cardiomyocytes. In fact, the rate of cardiomyocyte turnover in the adult human heart is about 2% per year between 20 and 40 years of age, and 0.5 -1% per year thereafter. While this rate of myocyte turnover is insufficient for heart regeneration following injury, it is critical for constant replacement of dead or damaged myocytes. As a result, close to 45% of cardiomyocytes in a human heart are replaced throughout its lifespan. We recently showed that an important mechanism of cell cycle arrest of the majority of cardiomyocytes postnatally is mitochondrial reactive oxygen species (ROS)-mediated oxidative DNA damage, and activation of DNA damage response (DDR). Moreover, we developed the first mouse model to fate map the rare population of cycling cardiomyocytes in the postnatal heart, and we found that these cycling cardiomyocytes are characterized by upregulation of hypoxic stress response and are protected from the oxidative DNA damage. Therefore, we propose to examine the mechanism of cardiomyocyte turnover in the adult mammalian heart using the fate-mapping model that we developed. We will first characterize the dynamics of hypoxic cardiomyocyte turnover in the neonatal, adult and ageing heart. We will also examine the role of DNA damage in regulation of hypoxic cardiomyocyte turnover. Finally, we will investigate the endogenous mechanism of maintenance of hypoxia signaling in cycling cardiomyocytes. Achieving the goals of this proposal will provide new insights into the mechanism of cardiomyocyte turnover in the adult mammalian heart. We hope to exploit these results to develop new strategies to enhance cardiomyocyte renewal in the failing heart.

Public Health Relevance

Regulation of mammalian cardiomyocyte cell cycle has been a central question in cardiovascular biology for decades, secondary to the burden of heart failure. Although the adult heart does not have a significant regenerative potential, it has recently become clear that measurable cardiomyocyte turnover occurs in the adult heart. In the current proposal, we have developed a new genetic tool, which allowed us to identify a rare population of specialized cardiomyocytes that mediate cellular turnover in the adult mammalian heart. We will use this model to gain insights into the mechanism of turnover in the adult heart, which has profound impact on cardiac pathology, and is critical for developing therapeutic strategies for treatment of heart failure.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL131778-01
Application #
9079266
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390