Molecular-level discovery about heart mechanisms could lead to new heart disease treatments

(Press-News.org) PROVIDENCE, R.I. [Brown University] — New findings by a team of molecular biologists at Brown University on the critical role of a protein called AIMP3 in heart function could inform new treatments for heart disease.

In a study published in Nature Cardiovascular Research, the researchers showed that removing AIMP3 from heart cells in mice led to severe heart problems, including inflammation, scarring and fatal heart failure.

“AIMP3 is a protein that had never been studied in the heart and was of unclear function,” said study author Federica Accornero, an associate professor of biochemistry at Brown who is affiliated with the University’s RNA Center. “What we discovered is that cardiac AIMP3 is crucial for survival.”

AIMP3 is part of a larger cellular machinery responsible for building other proteins. The precise functions of the proteins are unknown, but scientists suspected that AIMP3 affects how much protein the heart makes, Accornero said. Instead, the researchers discovered that AIMP3 is essential to avoiding mistakes in protein synthesis. The finding could have an impact even beyond the heart, she said, because AIMP3 could exert the same function in cells in other organs, as well.

In the project led by Anindhya S. Das, a postdoctoral research associate in molecular biology, cell biology and biochemistry, the Brown research team used gene editing techniques to “knock out” AIMP3 in mice and then observed the effects. 

They found that the key role of AIMP3 is to help another protein, MetRS, properly "edit" or remove a harmful substance called homocysteine. Without AIMP3, homocysteine builds up in heart cells, causing damage by inducing oxidative stress, protein aggregation and defective mitochondria, leading to cell death. When the researchers removed AIMP3 from heart muscle cells in mice, the mice developed severe heart problems and eventually died. 

“Overall, we uncovered a unique role of AIMP3 in maintaining the editing activity of MetRS and its essential role in heart function and survival,” Das said. 

These findings are significant, Das added, because they highlight a new and essential way AIMP3 protects the heart, and understanding the mechanism could lead to new treatments for heart diseases linked to homocysteine buildup. As next steps, the team is conducting studies in mice to determine how they might use the new discovery to develop preventative treatments for heart disease, starting with exploring whether having more of the AIMP3 protein would help the heart to better cope with stress.

Cardiovascular disease is the leading cause of death worldwide, Accornero noted. 

“The heart is a critical system to study, because there isn’t really an effective strategy to repair injury,” she said. “So the maintenance of the health of these cardiac cells is a really critical point.”

This research was funded by the National Institutes of Health (R01 AG079842, R01 HL136951, R01 HL154001, F30 HL165812) and the American Heart Association.

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