Abstract
Circular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are differentially expressed in post myocardial infarction (MI) mouse hearts including circFndc3b which is significantly down-regulated in the post-MI hearts. Notably, the human circFndc3b ortholog is also significantly down-regulated in cardiac tissues of ischemic cardiomyopathy patients. Overexpression of circFndc3b in cardiac endothelial cells increases vascular endothelial growth factor-A expression and enhances their angiogenic activity and reduces cardiomyocytes and endothelial cell apoptosis. Adeno-associated virus 9 -mediated cardiac overexpression of circFndc3b in post-MI hearts reduces cardiomyocyte apoptosis, enhances neovascularization and improves left ventricular functions. Mechanistically, circFndc3b interacts with the RNA binding protein Fused in Sarcoma to regulate VEGF expression and signaling. These findings highlight a physiological role for circRNAs in cardiac repair and indicate that modulation of circFndc3b expression may represent a potential strategy to promote cardiac function and remodeling after MI.
Highlights
Several potential therapeutic agents for post-MI repair have been investigated in recent years, including non-coding RNAs[2,3,4]
Using divergent primers and Reverse transcription (RT)-quantitative PCR (qPCR), we validated that several of these circRNAs were differentially expressed, including the 215-nt circFndc3b transcript that was significantly down-regulated in the post-MI hearts compared to sham controls (Fig. 1b and Supplementary Fig. 1)
Upon examining mouse hearts at different time point’s post-MI, we further found that circFndc3b expression continued to decrease throughout the follow-up period of 6 weeks post-MI compared to sham hearts (Fig. 1c)
Summary
Several potential therapeutic agents for post-MI repair have been investigated in recent years, including non-coding RNAs (ncRNAs)[2,3,4]. Circular RNAs (circRNAs) have recently been identified as a new class of regulatory RNAs with gene regulatory roles[5,6,7,8], their role in cardiovascular injury and repair is not well elucidated. Whether modulation of specific circRNAs in vivo can attenuate left ventricular dysfunction after experimental MI is not yet known To address this question, we used circRNA profiling of cardiac tissue from post-MI mice and identified circFndc3b (derived from exons 2 and 3 of the Fndc3b gene) as a circular RNA significantly downregulated post-MI. We provide evidence that circFndc3b enhances vascular endothelial growth factor-A (VEGF-A) expression and signaling via its interaction with the RNA binding protein fused in sarcoma (FUS)
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