Prostaglandin E receptor subtype 4 protects against diabetic cardiomyopathy by modulating cardiac fatty acid metabolism via FOXO1/CD36 signalling

Background: Cardiac fatty acid metabolism is essential for maintaining normal cardiac function at baseline and in response to various disease stress, like diabetes. EP4 is widely expressed in cardiomyocytes and has been demonstrated to play a role in cardio function. However, its function in regulating cardiac fatty acid metabolism is remained unknown. Methods: Mice were fed with standard chow or high-fat for eight weeks. The effects of EP4 deficiency on cardiac function, cardiomyocytes hypertrophy and myocardial fibrosis were studied. The possible regulatory mechanisms were further investigated. Results: EP4−/− mice exhibited concentric hypertrophy and myocardial fibrosis with cardiac energy deprivation due to reduction of fatty acid uptake and inhibition of ATP generation mediated by FOXO1/CD36 signalling. Moreover, pharmacologically activated EP4 alleviated impaired fatty acid transport and insufficient ATP generation in cardiomyocytes. Conclusion: EP4 tightly coordinates the rates of cardiac fatty acid uptake and ATP generation via FOXO1/CD36 signalling axis. Our study provides evidences for the link between EP4 and cardiac fatty acid transport and further pointed out that EP4 could be a potential target for modulating fatty acid metabolism and curbing cardiac tissue-specific impairment of function following diabetes.