Scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) and colleagues describe, reportedly for the first time, a circular RNA that fills a critical role in tissue repair after a heart attack, due to its ability to bind harmful molecules, including microRNAs and proteins. Their study (“Circular RNA CircFndc3b modulates cardiac repair after myocardial infarction via FUS/VEGF-A axis”) appears online in Nature Communications.

“We discovered that a circular RNA known as circFndc3b, when added therapeutically to the injured heart after surgically induced heart attack in mice, enhances cardiac repair and helps restore heart function,” explained Raj Kishore, PhD, professor of pharmacology and medicine and director of the stem cell therapy program in the Center for Translational Medicine at LKSOM and senior investigator on the new report. “We attributed these effects of circFndc3b to its ability to function like a ‘sponge,’ binding a protein called Fused in Sarcoma (FUS) that mediates cell death and reduces vascular growth, which hinders heart tissue repair.”

“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,” the investigators wrote.

“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 FUS 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.”

Kishore and colleagues focused their investigation on circFndc3b after finding that this particular circular RNA was significantly decreased in the heart in mice that had experienced a heart attack. “This observation led us to wonder whether the change in circFndc3b expression meant that it was important functionally in the heart,” Kishore said.

To investigate this possibility, a gene product to induce circFndc3b overexpression was injected into the heart in mice after heart attack. Subsequent examination showed that within eight weeks of injection, treated mice experienced gains in heart function and in survival compared to their untreated counterparts. There was also evidence within heart tissue that new blood vessels had started to form, greatly aiding the tissue repair process.

The findings offer insight into circular RNAs and the significance of their potential role as molecular sponges that limit the activity of damaging molecules. “CircFndc3b specifically soaked up an RNA binding protein that suppresses blood vessel formation,” Kishore explained. “In doing so, it made way for new vessels to grow.”

Kishore and colleagues are now in the process of developing a large animal model to further investigate the therapeutic potential of circFndc3b. The team also wants to begin analyzing plasma samples from patients just after heart attack to investigate whether specific circulating RNAs could serve as biomarkers for heart disease or injury and to get a better sense of their clinical significance.

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