Two chemicals boost cardiac regeneration in mice with heart failure

human heart

Gladstone Institute scientists have pinpointed two chemicals that help the heart convert scar tissue into healthy cardiac muscle. The discovery could lead to new treatments for heart failure, for which there is no cure.

Heart failure is characterized by the inability to pump enough blood to support the body. Current treatments to manage the condition include various drugs, such as blood pressure control meds and beta blockers, as well as receiving an implantable cardioverter-defibrillator and coronary artery bypass surgery.

The Gladstone team looked into cellular programming--turning one type of adult cell into another--and found that three transcription factors are needed to “reprogram” connective tissue cells to become heart cells in mice, according to a statement. The method, reported in the journal Circulation, uses the transcription factors Gata4, Mef2c and Tbx5 (GMT), effectively converting scar tissue back into healthy, beating heart tissue using the heart’s own cells.

While the regeneration of heart tissue is promising, the process has only a 10% success rate. After testing 5,500 chemicals, the scientists pinpointed two that not only boosted the number of heart cells generated eightfold, but also made the cell-conversion process up to eight times faster, cutting the duration down from six to eight weeks to just one week, according to the statement.

One of the chemicals inhibits a growth factor that plays a role in repairing tissue after injury, while the second blocks a pathway that regulates heart development. The team combined these chemicals with GMT, one of the transcription factors, and managed to regenerate heart muscle and recover heart function in mice that had had a heart attack, according to the statement.

"While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient," said senior author Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease, in the statement. "With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process."

“With our enhanced method of direct cardiac reprogramming, we hope to combine gene therapy with drugs to create better treatments for patients suffering from this devastating disease," said Tamer Mohamed, first author on the study and a former postdoctoral scholar at Gladstone, in the statement.