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ShareNov. 9, 1998 — DALLAS, Nov. 8 -- Scientists are finding ways to switch on and off key proteins that may make heart cells come out of biological "dormancy" and replace the damaged cells that result from heart disease. Their research was reported today in two presentations at the American Heart Association's 71st Scientific Sessions.
Unlike most other cells in the body, heart muscle cells, called myocytes, are believed to stop multiplying shortly after birth and do not regenerate, even if they are damaged, say the researchers. Because heart muscle cells can not generate new cells, they enlarge to accommodate growth of the heart and to take over the functioning of cells damaged by a heart attack or other conditions, such as high blood pressure, that stress the heart.
"After a heart attack, or in response to stresses on the heart, myocytes will get bigger. However, these bigger heart cells don't work as well," says W. Robb MacLellan, M.D., assistant professor in the Cardiovascular Research Laboratories at the University of California at Los Angeles School of Medicine.
"We're trying to find a way to get the cells to multiply instead of enlarge," he says. Cells that enlarge cause a condition known as left-ventricular hypertrophy, which can increase the risk of developing congestive heart failure.
MacLellan and colleagues say the research may lead to new "gene therapy" to treat heart enlargement and improve heart function in people who have heart disease.
Based on an earlier study suggesting that the "retinoblastoma" gene was critical in controlling cell division, MacLellan and his colleagues focused on the protein that this gene produces retinoblastoma protein, called Rb. Scientists believe the Rb protein may help keep heart cells "dormant" so they no longer can divide. To test this theory, MacLellan's group "turned off" the Rb in a group of mice. Researchers compared heart sizes between the genetically altered mice and mice who still had the Rb gene on in their hearts.
Scientists noticed that the heart cells continued to divide for a longer time in the genetically altered mice (those without the heart Rb gene). At eight weeks of age the hearts in mice without Rb were 8 percent bigger than the hearts of mice that still had the Rb gene active in their heart cells.
While this represents an important step forward in manipulating cells in the heart to grow, MacLellan says researchers still must investigate how the Rb gene works over time and whether these heart cells will multiply after a stress, such as heart attack.
Extending these studies, MacLellan and colleagues identified a protein in the heart that binds to Rb. Called MRP1, this protein appears to oppose Rb's effects in the heart and is turned off by binding to Rb. Although the full effects of this protein are to be determined, it appears that MRP1 can return cells to an earlier phase similar to fetal cells.
While fetal heart cells are capable of dividing, shortly after birth these cells stop dividing and express specialized "adult" genes. "We think Rb and MRP1 are key parts of this process. If we can turn on MRP1 in adult cells, we may be able to get them to 'think' they are fetal cells and start dividing," he says. "Now we are searching for the right combination of these factors to trigger cell division. We hope by overcoming Rb, possibly with MRP1, we can set the heart cells up so that with the right stimulus they will divide," MacLellan says.
They hope that the same signals that stimulate dormant heart cells to enlarge -- such as stress from high blood pressure or having to "take up the slack" for damaged cells after a heart attack -- may be able to stimulate cells treated with MRP1 to divide and replace the damaged cells, he says.
Co-authors are Michael Schneider, M.D.; Marc Voorjuis, Ph.D.; Peter Frenkel, M.D.; and Anton Berns, Ph.D.
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