Abstract P1115: Epicardial Signaling Regulates Myocardial Contractility Via Mirna

Abstract

Background: A congenital left ventricular aneurysm is a rare cardiac malformation that maycause heartfailure, ventricular wall rupture, ventricular arrythmia or sudden cardiac death. However, mechanisms of congenital left ventricular aneurysm are not known. Paracrinesignals from cardiomyocytes, such as a cardiokine, prokineticin-2, can activate EPDCsdifferentiation in adult heart to promote neovascularization. How the reciprocal interaction viaprokineticin and miRs from epicardium to cardiomyocytes affect heart growth and function,and how EMT-related events contributecardiomyocyte proliferation and function areunknown. MicroRNA (miR124) has an important role in the adult heart, however, its role incardiac development is unknown. Results: Here in this study, by deletion of a prokineticin-2 receptor PKR1 through epicardialcell linage tracing at the different developmental stages of mice embryos, we found that thesemice exhibited ventricular rupture and embryonic lethality. Indeed, miR-124 was significantlyupregulated in PKR1 -deficient epicardial cells both in vitro and in vivo , whereas ectopicexpression of these miRs in epicardial cells resulted in the reduced expression of SNAI2 andsubsequently led to impaired EMT and EMT-related events such impaired migration andincreased apoptosis. Wild type mice cardiomyocytes that were cultured in condition mediumderived from PKR1-deficient epicardial cells had a lower beating rate and contractility. Treatment of the cardiomyocytes with miR-124mimic exhibited the same phenotype, that wasrestored by miR-124 inhibitor, indicating involvement of mir124 in epicardium-cardiomyocyte communication and regulation of cardiomyocyte contractility. Conclusion: These finding reveals a key signaling pathway in which a cardiokine,prokineticin-2 promotes EMT to form EPDCs and their migration in an autocrine manner, andsupports myocardial growth and contractility through repressing miR124. Our study mayprovide novel insight in etiology of congenital defects and new strategies to promotemyocardial regeneration.