CARDIOMYOPATHY IN MALES DRIVEN BY CHRONIC IFN-G EXPOSURE IN A MOUSE MODEL OF AUTOIMMUNE DISEASE

Abstract

Cardiovascular diseases have been associated with a chronic inflammatory response and activated cell-mediated immunity. However, modeling these chronic inflammatory diseases has been difficult. Systemic lupus erythematosus (SLE), a disease that is driven by high expression of interferons (IFNs), notably both IFN-� and IFN-g, has a strong association with idiopathic cardiovascular disease. Lupus patients show a male prominence in heart disease and posthumously demonstrate indications of apparent myocarditis, a difficult to diagnose form of heart disease. We have developed a mouse model of male biased autoimmune cardiomyopathy showing a functional loss in cardiac muscle. AU nucleotide Rich Element replacement (ARE) mice have a genetic change that results in a chronic, elevated level of IFN-g in the circulation due to a substitution of the AU rich regulatory element within the IFN-g mRNA 3? UTR with random nucleotides. ARE mice present a novel model for lupus cardiomyopathy and show that the decline in cardiac function may be independent of infiltrate in myocarditis, highlighting it as being potentially a cytokine driven cardiomyopathy. Here I demonstrate male mice with our model of chronic IFN-g exposure have more severe symptoms than females where a heart failure with preserved ejection fraction develops acutely in response to stress, with an associated defect in glucose metabolism. Fatigue, a symptom often associated with autoimmune diseases and cardiomyopathies is also tied to this skeletal and cardiac muscle defect of metabolism. Furthermore, I show that chronic IFN-g exposure in males plays a role in the development of the observed fatigue and cardiomyopathy. The work in this thesis examines the effect of chronic interferon expression and sex hormones impact on the muscle cell mitochondrial pathways involving energetic metabolism and function to gain insight involved in the stress response to adrenaline and how it may impact fatigue and the development of cardiomyopathy. This study provides new insight into and offers new approaches towards the treatment of these diseases as a result of metabolic dysfunction in the host.