Date of Award

Spring 4-22-2025

Embargo Period

4-28-2027

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biochemistry and Pathobiology

College

College of Graduate Studies

First Advisor

Ge Tao

Abstract

Cardiovascular disease is the number one worldwide cause of death. Cardiomyocytes have a very low proliferative rate in the adult heart, which results in an inability to regenerate after injury. After an injury such as a myocardial infarction, lost cardiomyocytes are replaced by a fibrotic scar. The loss of contractility leads to cardiac dysfunction and remodeling long-term. The murine heart exhibits a transient regenerative window that is lost within the first week of life and serves as a model to identify key regulators of cardiac regeneration.

Oxidative stress, driven by high reactive oxygen species (ROS), has many pathological implications. However, ROS serve as signaling molecules that are critical for a multitude of cellular pathways. ROS levels increase in the early postnatal period due to environmental oxygen and a metabolic shift to aerobic respiration, which is thought to drive cardiomyocyte cell cycle arrest. This halt in cardiomyocytes’ progression through the cell cycle impedes these cells regenerative ability. At the same time, neonatal ROS stimulate mechanisms that drive adaptations crucial for cardiomyocyte maturation, including mitochondrial energetics, sarcomere organization, and metabolic transitions.

The following study aimed to determine the impact of neonatal ROS on subsequent cardiac injury response. Utilizing a variety of animal models, the data presented here elucidates a feedback loop between Rbx1, a component of the Nrf2 degradation complex, and Pitx2, a transcriptional target of Nrf2. The Nrf2, or nuclear factor erythroid 2–related factor 2, signaling pathway mediates cellular defense against oxidative stress by responding to fluctuations in cellular ROS levels. Moreover, this work highlights the beneficial role of ROS in oxidative priming of cardiomyocytes during the neonatal period. Once establishing that diminished ROS impairs injury response within the myocardium, we sought to determine a mechanism for this response. Bioinformatics analysis followed by immunostaining revealed that decreased neonatal ROS leads to reduced macrophage infiltration into the infarcted area following myocardial infarction (MI).

Together, the results suggest that neonatal ROS are crucial for cardiomyocyte maturation and subsequent injury response. Moreover, the data suggest that uninhibited antioxidant signaling impairs cardiac regeneration and this may be due to impaired immune cell recruitment. These novel findings go against long-held concepts concerning cardiomyocyte oxidative stress. As such, this work may inform how to properly treat patients with a predisposition for infarction.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Wednesday, April 28, 2027

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