An Investigation into How Anti-Fibrotic Agents Rescue Cardiac Insulin Resistance and Improve Cardiac Function in a High Fat Diet-Induced Obesity Murine Model

Abstract

In recent decades, there has been significant advancement in our comprehension of the extracellular matrix (ECM) in terms of its composition, structure, and physiological functions. Moreover, mounting evidence suggests that increased ECM deposition contributes to the pathogenesis of various diseases. Current research endeavours targeting the ECM hold promise for the development of novel therapeutic strategies to address challenging medical conditions. Diabetes and heart failure often coexist, exerting reciprocal influences on each other and thereby affecting disease progression and outcomes. Notably, insulin resistance emerges as a pivotal mediator in this bidirectional relationship between diabetes and heart failure, posing a significant risk factor for heart failure development through compromised cardiac insulin signalling pathways. However, the underlying mechanisms of insulin resistance in heart failure remain incompletely elucidated. A growing body of evidence implicates cardiac ECM remodelling in the pathogenesis of insulin resistance, necessitating the identification of novel therapeutic targets to mitigate or reverse cardiac IR and its associated dysfunction. In this thesis, I specifically tested the hypothesis that reducing heart ECM constituents using clinical and pre-clinical anti-fibrotic agents may alleviate cardiac insulin resistance and improve cardiac function. Results from my PhD study have revealed that pharmacological inhibition of ECM receptor integrin α5β1 enhances insulin signalling in H9C2 cells. Additionally, my studies with the mineralocorticoid receptor antagonist Eplerenone have demonstrated its effectiveness in regulating body weight gain and enhancing cardiac function in obese mice. My findings also establish a novel association between increased ECM deposition, cardiac insulin resistance, and cardiac dysfunction in obesity. Notably, pharmacological reduction of hyaluronan, a key ECM component, using pegylated human recombinant hyaluronidase PH20 (PEGPH20) has demonstrated its potential to ameliorate cardiac insulin resistance and associated functional impairments in obese mice. Further evidence was attained through genetic and pharmacological inhibition of the hyaluronan receptor RHAMM. Specifically, my results indicate that mice deficient of RHAMM (KO) exhibit improved glucose tolerance and lower aortic pressures compared to littermate wildtype (WT) controls, particularly in males fed a high fat diet (HFD). Cardiac ECM remodelling and functional alterations induced by HFD were attenuated in KO males. Conversely, such protective effects were not evident in female mice. The present findings underscore the therapeutic promise of early interventions aimed at cardiac ECM remodelling to alleviate cardiac insulin resistance and dysfunction associated with obesity. It is proposed that strategies intended to prevent pathological ECM expansion may confer protection against the progression to severe cardiovascular complications. As such, the implications of these findings are of considerable importance to the development of effective interventions targeting cardiac ECM remodelling in the context of obesity-associated cardiovascular disease.