P4 Genetic deletion of hyaluronan receptor RHAMM improves glucose tolerance and cardiac performance in vivo

Extracellular matrix (ECM) remodelling has recently emerged as an important contributor to insulin resistance. Systemic insulin resistance is associated with abnormalities in cardiac function. However, the role of cardiac ECM remodelling and insulin resistance in cardiac dysfunction is poorly documented. Our previous studies showed that inhibiting ECM collagen and hyaluronan deposition by clinical and preclinical antifibrotic drugs attenuated cardiac insulin resistance and dysfunction in high-fat diet (HFD)-induced obese mice. The present study examined the role of hyaluronan receptor RHAMM (Receptor for hyaluronan-mediated motility) on cardiac function and glycaemic control in both male and female mice. Whole-body RHAMM knockout (KO) mice and their wildtype (WT) littermate controls were fed a chow diet or 60% HFD for 16 weeks. Glucose metabolism was determined by glucose and insulin tolerance tests, and cardiac performance was determined by pressure-volume loop analysis. Body weight and body composition were not different between WT and KO mice on either diet or gender. Glucose tolerance was improved in the KO mice compared to WT mice in both diets and genders. Systolic and diastolic aortic pressures were lower in the KO mice compared to WT controls in both diets and genders. HFD caused an increase in the left ventricular end-systolic and diastolic volumes and a decrease in cardiac collagen deposition (interstitial and perivascular) in KO males relative to WT males. However, these changes were absent in the female mice. Instead, the heart size of the KO females appeared bigger than that of WT on HFD. These findings suggest that targeting ECM remodelling is a crucial regulator of glycaemic control and cardiac function in obesity.