How Gata4 helps mend a broken heart

August 15, 2017, Baylor College of Medicine
Credit: CC0 Public Domain

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 Dr. Megumi Mathison, associate professor of surgery at Baylor College of Medicine. "Our approach is to restore by reprogramming into cardiomyocytes."

In the Laboratory for Cardiac Regeneration, led by Dr. Todd K. Rosengart, professor and chair of surgery and professor of molecular and cellular biology at Baylor, a team of researchers has shown that administration of a cocktail made of transcription factors Gata4, Mef2c and Tbx5 (GMT) results 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.

A novel role for Gata4

"We and others had described that, in addition to inducing reprograming of fibroblasts into cardiomyocyte-like cells, the GMT cocktail also induced reduction of post-heart attack fibrosis," Mathison said. "However, not much attention had been paid to the latter."

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.

"Gata4 plays a complex role in heart regeneration: as part of the GMT cocktail, it contributes to the reprograming of fibroblasts into cardiomyocyte-like cells; we know it contributes to heart hypertrophy - the development of an enlarged - and now we discovered that it alone can decrease cardiac fibrosis," Mathison said. "Others have reported that Gata4 also can suppress liver . There is still a lot to be done before we can transfer these discoveries to the bedside, but they are important first steps."

Explore further: Root of cardiac fibrosis defined

More information: Megumi Mathison et al, Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail, The Journal of Thoracic and Cardiovascular Surgery (2017). DOI: 10.1016/j.jtcvs.2017.06.035

Related Stories

Root of cardiac fibrosis defined

July 13, 2017
Northwestern Medicine scientists have identified a novel molecular mechanism that regulates scar formation in the heart, a common manifestation of aging and nearly every form of heart disease. The discovery was published ...

Study hints at experimental therapy for heart fibrosis

August 14, 2017
Researchers report encouraging preclinical results as they pursue elusive therapeutic strategies to repair scarred and poorly functioning heart tissues after cardiac injury—describing an experimental molecular treatment ...

Fibroblasts reprogrammed into functioning heart cells in mice

April 23, 2012
(HealthDay) -- Cells that normally form scar tissue after a heart attack can be reprogrammed into functional heart cells in mice, according to an experimental study published online April 18 in Nature.

A pathway controlling inflammatory responses aids recovery after heart attack

February 6, 2017
After a heart attack, or myocardial infarction, a patient's long-term prognosis depends on the ability of the heart tissue to heal and remodel. Immune system activation and inflammatory responses that occur in the aftermath ...

Research reveals new insights into why the heart does not repair itself

June 5, 2017
Heart muscle is one of the least renewable tissues in the body, which is one of the reasons that heart disease is the leading cause of death for both men and women in the United States, according to the Centers for Disease ...

Gene therapy reprograms scar tissue in damaged hearts into healthy heart muscle

January 4, 2013
A cocktail of three specific genes can reprogram cells in the scars caused by heart attacks into functioning muscle cells, and the addition of a gene that stimulates the growth of blood vessels enhances that effect, said ...

Recommended for you

Height may be risk factor for varicose veins, study finds

September 24, 2018
The taller you are, the more likely you are to develop varicose veins, according to a study led by Stanford University School of Medicine researchers that examined the genes of more than 400,000 people in search of clues ...

Physical activity necessary to maintain heart-healthy lifestyle

September 24, 2018
Exercise and physical activity are of vast global importance to prevent and control the increasing problem of heart disease and stroke, according to a review paper published today in the Journal of the American College of ...

Prosthetic valve mismatches common in transcatheter valve replacement, ups risk of death

September 24, 2018
In the largest multi-institutional study to date, led by researchers from Penn Medicine, the team found that among patients who underwent a transcatheter aortic valve replacement (TAVR), a high number experienced severe and ...

Study reveals a promising alternative to corticosteroids in acute renal failure treatment

September 21, 2018
A protein produced by the human body appears to be a promising new drug candidate to treat conditions that lead to acute renal failure. This is shown by a study conducted at São Paulo State University (UNESP) in São José ...

Can a common heart condition cause sudden death?

September 20, 2018
About one person out of 500 has a heart condition known as hypertrophic cardiomyopathy (HCM). This condition causes thickening of the heart muscle and results in defects in the heart's electrical system. Under conditions ...

New drugs could reduce risk of heart disease when added to statins

September 20, 2018
New drugs that lower levels of triglycerides (a type of fat) in blood could further reduce the risk of heart attack when added to statins. These new drugs, which are in various stages of development, could also reduce blood ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.