HARVARD GAZETTE ARCHIVES

Heart-muscle cells, or cardiomyocytes, were previously considered incapable of replicating in mammals after birth, which is why heart attack is such a problem: Once killed, heart tissue can't regenerate. Mark Keating and Felix Engel now show that an enzyme known as p38 MAP kinase suppresses cardiomyocyte replication, and that inhibiting p38 enables these cells to proliferate. Their report appears in the May 15 issue of Genes & Development (published online May 3).

Keating, Engel, and colleagues first showed in fetal rats that increased p38 activity correlates with reduced cardiac growth, and that reduced p38 activity correlates with accelerated cardiac growth. Then, working with adult cardiomyocytes, they demonstrated p38's role in every major step of cell replication.

First, in cultures of cardiomyocytes from rats, they showed that activation of p38 reduced DNA synthesis, the first key step in cell replication. Further, inhibition of p38 increased DNA synthesis. Second, they showed that p38 regulates the activity of genes required for mitosis (division of the cell nucleus in two), a second key step in replication. When mice were bred to lack p38, mitosis in their cardiomyocytes increased by more than 90 percent. Finally, p38 inhibition promoted cytokinesis, the last step of replication in which the entire cell divides to form two separate cells. Growth factors were needed to get the full effect.

"This is just one baby step toward regenerative therapy, but it's an important one," says Keating. "Inhibiting p38 is now a candidate therapeutic strategy."

When a human heart is injured, it cannot ''grow back'' the damaged muscle, which is instead replaced by scar tissue. Too much scarring can impair the heart's ability to pump and can lead to life-threatening arrhythmias. "If you want to prevent hearts from becoming scarred, a regenerative therapy is needed," Keating says.

Keating, Engel, and colleagues are now studying rodents with simulated heart attacks to see whether agents that inhibit p38 would improve heart function and induce heart regeneration with reduced scar formation. Keating believes this approach, if successful, would prove more practical than stem-cell therapy, which would involve implanting whole cardiomyocytes.

"From a practical perspective, we think that delivering proteins or small molecules is much more likely to succeed," he says. "It would be like taking the drug epoetin alfa to stimulate red blood cell production as opposed to getting a blood transfusion. Instead of borrowing cells, you're making them yourself."

The p38 enzyme was chosen for study because it is known to be important in the differentiation of cardiomyocytes. Once cells differentiate into their mature form, they usually lose their ability to proliferate. This study shows that ability can be revived.