The effects of high-fat diet induced insulin resistance on cardiac structure, function, and lipid profile

Intracardiac injection of recombinant EphrinA1-Fc immediately following coronary artery ligation in mice reduces infarct size in both reperfused and non-reperfused myocardium. These protective effects occurred via modulation of the inflammation, autophagic, and apoptotic signal cascades as well as interstitial fibrosis. Given the prevalence of heart disease and poor prognoses in the diabetic population, this project aims to understand the effects of a high-fat diet(HFD) on the heart and cardiac lipid profile and mechanism by with HFD models are associated with poorer outcomes to investigate the potential therapeutic utility of ephrinA1-Fc in the diabetic, ischemic heart. 5-6 wk-old C57BL6J male and female mice were fed a high-fat diet for 12 weeks to induce insulin resistance. Echocardiography was conducted to measure cardiac structure and function. Mice were sacrificed and hearts were either frozen or embedded in paraffin. Glycogen content assays and liquid-chromatography mass spectrometry (LC/MS) were conducted on frozen hearts to assess glycogen content and cardiac lipid profile. Immunohistochemistry and histology staining were conducted on fixed tissue sections to assess inflammation and fibrosis. Male HFD mice experienced a significant reduction in ejection fraction and fractional shortening and a significant increase in systolic and diastolic chamber dimensions, while female HFD mice exhibited decreased LV mass/body weight ratio. Male HFD models exhibited altered structure and inflammation levels, as evidenced by increased inflammation, fibrosis, and hypertrophy/myocyte cross-sectional area, which can reduce cardiac function and remodeling capacity. HFD mice displayed a significant decrease in cardiac glycogen content. A significant increase in LDMPE peak area was observed in HFD mice. Preliminary in vitro studies using H9c2 cells treated with estradiol suggest that time and dose of ephrinA1 may influence estradiol mediated changes in ephrinA1/EphA. From these results, it is possible that EphrinA1-Fc (EA1) could be used to combat the impairment caused by HFD feeding. Further studies are necessary to investigate the cardiac modeling consequences of injecting a therapeutic dose of EphrinA1-Fc at the time of myocardial infarction in HFD models