An Examination Of Mechanisms Contributing To Cell Death Induced By Metabolic Stress In Cardiomyoblasts And Immune Cells

Abstract

Metabolic syndrome is an underestimated, growing global health crisis, plaguing millions of people worldwide. In this thesis, I assessed mechanisms of two important features of metabolic dysregulation; hyperglycemia and iron overload. This was accomplished across three projects; 1) examining mechanisms of adiponectin action in attenuating high glucose-induced cell death in cardiac cells and tissue, 2) observing inflammatory response in macrophages upon combining high glucose and iron treatments and 3) examining shifts in frequency of immune cell subsets in PBMCs treated with high glucose and iron. Briefly, results from study #1 revealed that an adiponectin mimetic, ALY688, was able to successfully attenuate high glucose-induced cell death in cardiomyoblasts and ventricular mouse tissue, in an autophagy-dependent manner. Interestingly, inflammatory agents released from cardiomyoblasts were eliciting inflammatory pathway activation in macrophages, which led to the formation of study #2. This study explored how two relevant metabolic stressors, high glucose and iron, could induce inflammation in macrophages. This study found that combining high glucose and iron led to significant activation of key inflammatory pathways, cytokine release and cell death in bone marrow-derived macrophages. These findings became the foundation for the next study to elucidate whether this robust response would be observed in primary human immune cells; peripheral blood mononuclear cells (PBMCs). Results from this study found no significant difference in frequency of T cells, though frequency of natural killer T cells were elevated upon treatment with high glucose and iron. In addition, combining high glucose and iron in PBMCs resulted in a profound increase in cytokine production, oxidative stress, mitochondrial dysfunction, and cell death. Overall, this thesis elucidates mechanisms of cellular damage induced by highly relevant metabolic stressors in cardiomyoblasts and immune cells. It further evaluates a therapeutic intervention and provides insight into axes that can be investigated to combat adverse metabolic outcomes.