DEFINING THE ROLE OF IRON-DEPENDENT CELLULAR INJURY IN CARDIOMYOCYTES

Abstract

Heart failure remains one of the leading causes of death in America and while advancements in preserving patient outcomes after myocardial infarctions are improving the adverse effects after a myocardial infarction are still prevalent. To develop better therapeutic approaches, greater understanding of ischemia-reperfusion (I/R) injury and its mechanism will be required. In this dissertation, I aim to better understand cell death and scarring relating to I/R injury and determine if ferroptosis plays a significant role in that cell death cascade in cardiac I/R injury. To do this we used a handful of models to determine the unique patterning of scarring in I/R injury and discern if ferroptosis plays a major role in its formation. Initially we examined a set of human cadaveric hearts with and without percutaneous coronary intervention (PCI) and discerned that PCI resulted in scarring following myofibers instead of coronary arteries. We then used a murine in vivo model to determine that scarring along myofibers was consistent with I/R injury and occurred in the early phases of LV remodeling. Next, we developed a novel in vitro model of injury extending from cell-to-cell to determine the role of ferroptosis. Through this model we saw that ferroptosis was a major factor to cell death extending from cell-to-cell. Lastly, we used an ex vivo model to induce I/R conditions and saw that ferroptosis inhibitors were sufficient to prevent cell death along myofibers, solidifying that ferroptosis is a major factor in the fibrotic scarring that extends along myofibers. However, a clear mechanism of how ferroptosis extends cell death or what is communicated between cells still needs to be identified. Better understanding of ferroptosis in I/R injury could bring new therapeutic insights into combatting heart failure.