Worm enzyme has promise for patients with cardiovascular disease

December 11, 2002

The simple worm has at least one talent that could benefit most Americans.

It can convert Omega-6 - a group of fatty acids abundant in the Western diet with the potential to promote inflammation - into Omega-3, another class of fatty acids that decreases inflammation, helping keep vessel walls smooth and blood free-flowing.

The question one Medical College of Georgia researcher is asking is whether the enzyme these C. Elegans, or nematodes, use can work the same magic in people.

Dr. Steffen E. Meiler and his colleagues at Massachusetts General Hospital and Harvard Medical School have found, at least in laboratory studies of human endothelial cells, that this enzyme, fat-1, can halve the number of white blood cells that can adhere to the surface of blood vessel walls, laying a foundation for vascular disaster.

Dr. Meiler, an anesthesiologist and critical care specialist, got interested in the process that turns blood vessel linings from Teflon to Velcro because of the increased incidence of heart attack, stroke and deadly heart rhythms following surgery in patients with known cardiovascular disease.

The last decade of science has provided solid evidence that inflammation plays a role in cardiovascular disease in general; Dr. Meiler believes inflammation may also be the culprit that puts some people at risk following surgery.



"Our working hypothesis is that the vascular endothelium becomes activated or inflamed after surgery and begins to react with blood components, such as white blood cells, setting the stage for high-risk cardiac complications, such as a heart attack," said Dr. Meiler, vice chairman for research for the MCG Department of Anesthesiology and Perioperative Medicine. "Something about anesthesia and surgery and the type of morbidity that these patients bring makes this happen acutely. And right now there is no way we can protect the endothelium in the perioperative window."

But what he and his colleagues are finding may one day provide that protection.

Their work, funded by the National Institutes of Health, was selected for the American Heart Association's Best of Scientific Sessions 2002, honoring the top scientific studies presented at the association's Nov. 17-20 annual meeting.

Cardiologists already recommend more Omega-3 - found in high concentrations in fish such as salmon, mackerel and tuna - in the diet, through supplements or both. But most Americans likely consume far more Omega-6, found in high levels in foods such as beef, margarine, mayonnaise and vegetable oils. Native Alaskans, with fish-rich diets and low rates of cardiovascular disease, are good examples of the vessel-protecting potential of the Omega-3 polyunsaturated fatty acids.

Abundant evidence accumulated in animal and clinical studies shows that Omega-3 protects vessels by exerting an anti-inflammatory effect; it's also a powerful anti-arrhythmic. In fact, it's also been shown beneficial in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.

Inflammation, part of the body's natural response to injury, appears to have a fairly early role in cardiovascular disease. Fatty streaks in the vessels are often the earliest signs of disease that may one day mature into vessel-narrowing plaque, a nasty concoction of monocytes, lymphocytes, cholesterol, lipids, debris, excess smooth muscle cells and more.

"Inflammation probably sets in at the time when early streaking starts," Dr. Meiler said, probably because the early fat deposits evoke that response. But in cardiovascular disease, inflammation goes unchecked and becomes self-promoting. The Teflon-like endothelial lining of the blood vessels express adhesion molecules that create a sticky trap for white blood cells floating by in the bloodstream. The ones that stick can then migrate into the vessel wall to do their inflaming work.

"What is known is that blood vessels that are exposed to high cholesterol and that already have developed a certain stage of arteriosclerosis will already be pre-inflamed," Dr. Meiler said. "These cells are not normal. It is our hypothesis that when you add surgery in these folks, these cells will respond particularly vigorously and develop an endothelial inflammatory phenotype that will then cause more interaction with white blood cells and may lead to myocardial infarction."

That's where the worms come in.

Worms need a lot of Omega-3 to develop and, in contrast to humans and other mammals, they can convert Omega-6 to Omega-3, using the fatty acid desaturase fat-1.

So the scientists took the fat-1 enzyme and, using a virus as a delivery mechanism, put it into human endothelial cells, then added Omega-6 and stimulated the inflammatory process. They found, at least in culture, that the worm enzyme could convert Omega-6 fatty acids to their protective Omega-3 counterparts in human vascular endothelial cells as well.

Then the researchers wanted to look specifically at the level of inflammation as evidenced by the endothelium being transform from smooth to sticky. They looked at three surface-adhesion molecules important in trapping white blood cells and, again, fat-1 dramatically reduced these inflammatory markers on the surface of the human endothelium.

Next, just to make sure that this reduced level of adhesion molecule expression translated to fewer white blood cells sticking to the walls, they mimicked what goes on inside the vessels by putting the endothelial cells in a chamber with monocyte-rich fluid flowing over them. That's when they noted the 50 percent reduction in sticking of these cells that cause much of the inflammatory damage.

The next step is to develop a transgenic mouse that expresses fat-1 and see if the findings translate to a whole organism.

"The overriding question is how acute endothelial inflammation affects perioperative management," he said. Whether a genetic approach, as taken by Dr. Meiler and his colleagues, to change the lipid profile of human endothelial cells will ever become a practical consideration, remains to be seen.

However, "Our results have stirred a lot of excitement and we are eager to continue our work in this area," Dr. Meiler said.
-end-


Medical College of Georgia at Augusta University

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