Abstract 288: Circular RNA CircFNDC3b Modulates Cardiac Repair After Myocardial Infarction via FUS-1/VEGF-A Axis

Abstract

Circular RNA (circRNA) is a new addition to the list of growing body of non-coding RNAs.Recent studies highlighted that circRNA are dysregulated in cardiovascular disease. However,knowledge of the role of circRNAs in ischemic cardiac injury is limited. Using global circRNAexpression profiling, we identified several circRNA transcripts that were differentially regulatedpost-MI in mice, including circFNDC3b (derived from 2 and 3 exons of cognate FNDC3b gene)which is significantly down regulated. Cell fractionation experiments revealed that circFNDC3bis highly enriched in endothelial cells of post-MI mice. Notably, we found a circFNDC3b orthologin humans, which was also significantly down regulated in ischemic cardiomyopathy patients.Further, gene profile analysis of circFNDC3b overexpression in cardiac endothelial cellsdemonstrated an increase in angiogenic genes. Among them, vascular endothelial growthfactor-A (VEGF-A) was significantly elevated concomitant with reduced in vitro apoptosis ofcardiomyoblasts and endothelial cells, which also exhibited enhanced tube formation. Forcardiac overexpression of circFNDC3b, we generated AAV9 viral particles and found that in vivoover expression attenuated LV dysfunction post-MI and enhanced neovascularization.Mechanistically, circFNDC3b interacts with its potential target RNA binding protein FUS-1 (fusedin sarcoma) and regulate VEGF signaling, thereby reducing cardiomyocyte apoptosis andenhancing neovascularization and cardiac function post-MI. These results indicatethat circFNDC3b is a novel potential target to prevent cardiac remodeling and highlight theimportance of circRNAs in cardiovascular diseases.