Nov. 4, 1998 By Melanie Fridl Ross
GAINESVILLE, Fla.---A form of genetic trickery blocks the action of a harmful hormone, protecting the heart from the ravages of reduced blood flow, report University of Florida researchers, who describe results from a novel animal study in the American Heart Association's journal Circulation Research.
The treatment, the first application of gene therapy to the type of injury associated with a heart attack, also guards against the damage ironically caused when restoration of blood flow ferries a destructive oxygen molecule to the heart muscle.
While it may be years before the approach is tested in people, the study reflects increasing interest in the potential benefits of gene therapy, the current subject of intense scientific scrutiny.
The research team, which includes members from UF's College of Medicine and the Gainesville Veterans Affairs Medical Center, also hopes the method represents a first step toward improving the prevention and treatment of heart attacks in humans. Each year, 1.1 million Americans experience a heart attack, and about one-third die, according to the National Heart, Lung, and Blood Institute.
A key part of that effort is finding a way to impede the action of angiotensin, a hormone made in all body tissues that causes blood vessels to narrow, increasing blood pressure. Reduced blood flow to the heart is known as ischemia, and it can lead to heart attack.
"First you get ischemia, which is a lack of oxygenated blood supplying the heart tissue," said M. Ian Phillips, professor and chair of physiology at UF's College of Medicine. "And if you save a person who is having a heart attack, their blood begins to flow again, but that in itself causes damage, and it's unavoidable. It's because the oxygen the restored flow brings is a type of oxygen molecule called a superoxide, which actually destroys cells in the heart, further weakening the heart muscle."
Angiotensin acts at specialized sites, known as angiotensin receptors.
"Research in the last five to 10 years has shown that when angiotensin acts on these sites, it results in growth of the smooth muscle cells in the blood vessels as well as the heart muscle," said Dr. Jawahar Mehta, a professor of medicine, physiology and cardiology at the College of Medicine and the VA Medical Center. "And that way, excessive formation of angiotensin or greater activity can be responsible for blood vessel narrowing and enlargement of the heart. These are very common problems that have been identified." Mehta will present research results at the American Heart Association Meeting Nov. 8-11 in Dallas.
Accordingly, physicians currently treat patients with drugs that either inhibit the formation of angiotensin - angiotensin-converting enzyme inhibitors - or those that block the site where angiotensin acts, called angiotensin receptor blockers. These medications need to be taken two to three times daily and often have a large number of side effects, such as persistent cough.
Earlier UF research has shown that a brief period of reduced blood flow to the heart, akin to a heart attack in humans, results in the formation of two to three times more angiotensin receptors.
"Armed with that knowledge, we thought if we could design a therapy that would block the gene of that receptor (or that site) that would prevent the ischemic injury. And that's what we did," Mehta said.
So UF scientists treated rats with a molecule Phillips designed, referred to as antisense DNA, a type of reverse genetic message.
"The antisense is basically a genetic trick where the normal message for the receptors is given the opposite message, so fewer receptors are produced," Phillips said. "Apparently, that is what makes the heart pump much better."
The approach not only worked-it outperformed standard drug therapy using the medication losartan, which inhibits production of angiotensin receptors, he said. An added plus: A single dose of the gene therapy was long-lasting and showed no sign of the problems typically associated with angiotensin-converting enzyme inhibitors or other chemical blockers of angiotensin receptors.
"Our effects were much stronger than with the drug," Phillips said. "In fact, they were statistically significantly about twice as effective."
The next step is to see whether the methods of delivering this type of gene therapy to animals can be improved, Phillips said. Researchers also will evaluate the optimal time for administering the treatment in the time leading up to a heart attack. In addition, they will begin to assess whether gene therapy directed at halting the formation of angiotensin also is effective.
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