A protein cocktail that helps mend a broken heart

A team of researchers has uncovered a novel role for transcription factor Gata4 in reducing the post-heart attack fibrosis.

During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart weakens; most people who had a severe heart attack will develop heart failure, which remains the leading cause of mortality from heart disease.

"Our most important goal is to treat post-heart attack cardiac failure," said researcher Megumi Mathison from Baylor College of Medicine. "Our approach is to restore cardiac function by reprogramming scar tissue into cardiomyocytes."

In the Laboratory for Cardiac Regeneration, led by Todd K. Rosengart, a team of researchers showed that administration of a cocktail made of transcription factors Gata4, Mef2c and Tbx5 (GMT) resulted in less scar tissue, or fibrosis, and up to a 50 percent increase in cardiac function in small animal models of the disease.

This result was presumed to be mostly a consequence of the reprograming of heart fibroblasts into cardiomyocyte-like cells. Interestingly, the Rosengart team noticed that reduced fibrosis and improved cardiac function far exceeded the extent of induced new cardiomyocyte-like cells. "This observation suggested the existence of unexplored and non-optimized underlying mechanisms," Rosengart said.

The research team investigated in more detail how the GMT cocktail activated mechanisms that reduced fibrosis. They found the first evidence that, of the three components in the GMT cocktail, only Gata4 was able to reduce post-heart attack fibrosis and improve cardiac function in a rat model of heart attack.

Further exploration of the molecular mechanism mediating this novel effect showed that administering Gata4 to rat fibroblasts in the lab resulted in reduced expression of Snail, the master gene of fibrosis.

The study appears in the Journal of Thoracic and Cardiovascular Surgery.