Blocking a specific protein prevents severe heart failure in mice

Most heart failure cases are caused to a large degree by a build-up of excess scar tissue in the heart, which currently has no treatments.

Now, researchers have successfully prevented the development of severe heart failure in a mouse model of heart attack by blocking a protein that triggers the formation of excessive scar tissue.

Reducing the level of this protein, called AEBP1, after a heart attack or prolonged hypertension, could be a promising therapy to prevent heart failure development.

For the first time, we show that if we suppress AEBP1, it prevents heart failure progression and preserves cardiac function. We need to do more research and long-term studies, but there is potential for AEBP1 as a therapeutic target to suppress or slow down heart failure progression."

Thirupura Shankar, PhD, postdoctoral researcher in the Nora Eccles Harrison Cardiovascular Research Training Institute, University of Utah Health and first author on the study

The results are published in Nature Communications.

Lowering AEBP1 improves heart function in mice

The new results show that lowering the level of AEBP1 in the body helps keep the heart stronger and more functional after heart attack-like injury by preventing excessive scarring, or fibrosis. When the researchers lowered AEBP1 levels in fibroblasts-the cells that produce scar tissue-after mice had a heart attack, heart function was significantly better four weeks later.

However, when the researchers lowered AEBP1 levels after heart failure had already progressed, there was no improvement in heart function, suggesting that blocking the protein can prevent unhealthy scarring but not reverse it.

The team also identified some of the pathways by which AEBP1 might impact heart function, including by regulating a variety of genes involved with unhealthy scarring. These findings show how heart failure progresses and suggest additional targets for future therapies to treat or prevent heart failure.

AEBP1 may drive cardiac scarring in people

Evidence suggests that AEBP1 might also drive fibrosis in the human heart. The research team found that the AEBP1 gene is more active in the hearts of people with advanced heart failure. What's more, the protein produced by the AEBP1 gene is highest around areas of heart injury.

Promisingly, changing the level of AEBP1 in human heart tissue culture also impacted heart cells, the researchers found. In healthy heart tissue, increasing the level of AEBP1 changes the appearance of heart cells in ways that resemble heart failure. Conversely, when researchers decreased AEBP1 levels in samples donated by heart failure patients, the cellular architecture looked healthier and the level of scarring decreased.

This indicates that the results in mice might translate to improved heart failure therapies for people.

Working toward future therapies

The research team emphasizes that turning off all fibrosis is the wrong strategy. In the immediate aftermath of a heart attack, some scarring is necessary to keep the heart structurally sound. The problem is that overactive fibroblasts can keep producing scar tissue beyond what's needed, leading to heart failure. Instead of blocking fibrosis entirely, the team's goal is to allow early fibrosis and then stop overactive fibroblasts from creating an unhealthy level of scarring.

"Fibrosis is part of healing," explains Stavros Drakos, MD, PhD, professor of medicine at U of U Health, senior author on the study, and Shankar's mentor. "We need to first complete the healing, and then do the anti-fibrotic process. Future studies will be needed to determine the optimal timing of AEBP1 reduction to maximize heart function after a heart attack."

More work is also needed to test if targeting AEBP1 would have positive effects in people. The researchers think that their results could ultimately lead to better therapies for a common and hard-to-treat condition.

"There is no treatment or therapy for fibrosis in the heart, and AEBP1 shows a promising role in other organs too," Shankar says. "The fact that we're starting to see something similar in the heart is exciting."