Oxidative DNA Damage Regulates Cardiomyocyte Proliferation

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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.