New research suggests circular RNAs are important for cardiac healing

By Samantha Black, PhD, ScienceBoard editor in chief

September 20, 2019 -- Researchers from the Lewis Katz School of Medicine at Temple University describe how circular RNA fills a critical role during tissue repair after heart attacks, due to a unique ability to absorb harmful molecules. The study was published September 20 in Nature Communications.

Cardiovascular disease is a leading cause of death in the United States, responsible for every one in seven deaths. The need to understanding the molecular mechanisms behind heart disease and develop more effective therapies is urgent.

One potential therapeutic target for post-heart attack repair is non-coding RNA. Non-coding RNAs are not involved in protein synthesis. Recently circular RNAs (a type of noncoding RNA) has been discovered. These covalently closed transcripts are naturally resistant to degradation by exonucleases by most are expressed at low levels. Initially they were thought to be nonfunctional, but recent evidence suggests otherwise. For example, some circular RNAs have been shown to sequester specific microRNAs or RNA-binding proteins, or directly interact with regulatory proteins.

The current research supports that circular RNA may act like sponges to "soak up" or bind other molecules, including microRNAs and proteins. "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 Temple and senior investigator on the new report.

The research team selected circFndc3b after discovering that levels of this particular circular RNA were decreased in the heart of mice who experienced a heart attack. The Fndc3b gene is upregulated in certain cancers and is involved in survival signaling pathways. To investigate if changes in circFndc3b expression had functional importance in the heart, the researchers induced overexpression of circFndc3b. To do so, they injected a circFndc3b gene product into the heart of mice after a heart attack.

In post-heart attack mice, researchers observed increased in the left ventricle tissue with significant restoration of left ventricle dimension. The researchers also found 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.

This research presents exciting insight into how circular RNAs could act as molecular sponges that limit the activity of damaging tissues. The research team is 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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