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New Player in Heart Disease Found

Molecular variation of ACE enzyme linked to hypertension

WEDNESDAY, June 19, 2002 (HealthDayNews) -- The genetic picture of high blood pressure and heart disease just got more complicated with the discovery of a molecular variation on the theme of the angiotensin-converting enzyme.

Most people with high blood pressure have at least a passing knowledge of angiotensin-converting enzyme (ACE) because many of them are taking ACE inhibitors to help keep the pressure down. ACE inhibitors, as their name implies, inhibit the activity of the ACE enzyme, which acts on a protein called angiotensinogen to produce angiotensin. That, in turn, tightens arteries and raises blood pressure.

Now, it turns out that more than one enzyme acts on angiotensinogen; with scientific brevity, it has been given the name ACE 2. Both ACEs act in the same way, clipping amino acids off the angiotensinogen enzyme. However, the original ACE clips off two amino acids, and ACE2 clips off one. The result is a molecule with a strikingly different set of activities that are just beginning to be explored.

Researchers at the University of Toronto in Canada have been doing the exploration. They have created mice that lack the gene for ACE 2 and have done detailed studies of what happens to those mice, reporting the results in tomorrow's issue of Nature.

It turns out mice that carry the gene for ACE 1 but not ACE 2 develop impaired heart function. "They have a severe defect in heart function, the mechanism of which we don't know," says Michael A. Crackower, a postdoctoral fellow and a member of the research team.

A statement by Dr. Josef Penninger, a professor of biophysics at Toronto and leader of the research effort, says one logical explanation is the product of the ACE 2 gene protects against previously unidentified damaging side effects of the ACE 1 product. While ACE 1 does lower blood pressure, it also appears to generate molecules that attack the heart, he says.

"What I found interesting is that the hearts in our mice looked like human ones with coronary heart disease," Penninger says. "The transgenic mouse models created in these studies can now be used to develop new approaches to heart disease therapy and new approaches to genetic screening to determine if people are at risk for heart disease and heart failure."

ACE 2 also appears to play a role in high blood pressure, Crackower says. Previous studies have identified the location of a not-yet-identified gene closely involved in high blood pressure. The ACE 2 gene is in that region, which makes it "a strong candidate" for that role, Crackower says.

One immediate goal of ACE 2 research at Toronto is "to determine the mechanism that causes the heart defect," he says. The current theory is the trouble is caused by a reaction that deprives the endothelium, the delicate outer layer of heart muscle, of an adequate supply of oxygen.

The discovery of ACE 2 "raises new questions that may lead to radically new insights," says Dr. Kenneth E. Bernstein, professor of pathology at Emory University and author of an accompanying editorial.

"Finding that an enzyme had an effect on the heart was very exciting," he says. "When you see something unexpected, it opens new ways of thinking."

There is a classic sequence in scientific discovery, Bernstein says; first, a major discovery, then the longer work of understanding all the implications of that discovery. "This discovery clearly means that something is going on that we need to understand," he says. "When we understand it, we can start to manipulate it."

Is there a new kind of drug for high blood pressure on the horizon? One hint comes from Crackower's plans. He is about to start working for Amgen, the California-based biotechnology company that helped finance the research.

What To Do

You can learn about existing ACE inhibitors from the Austin Heart Group. Meanwhile, the American Heart Association has a page on drugs that lower blood pressure.

SOURCES: Michael A. Crackower, Ph.D., postdoctoral fellow, University of Toronto; Kenneth E. Bernstein, M.D., professor, pathology, Emory University, Atlanta; June 20, 2002, Nature
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