Study Points to Heart Disease Marker's Dark Side

Scientists have taken a small step in identifying an additional potential cause of heart disease.

Whether or not the possible culprit, C-reactive protein (CRP), actually does damage in humans is still an open question, however.

"The big prize is nailing [CRP] as a cause of heart disease and not just a marker," said Dr. Edward Fisher, a professor of medicine at New York University School of Medicine, and national spokesman for the American Heart Association. "A lot of people are working on it, and we're not there yet."

The study outlining the latest findings appears in the July issue of Arteriosclerosis, Thrombosis, and Vascular Biology.

CRP is established as a marker for heart disease, meaning it can identify people at high risk for heart attacks, strokes and other events. Proving a more active role has so far proved elusive.

Blood levels of the protein increase when parts of the body become inflamed. Inflammation, in turn, is key to the development of atherosclerosis. As such, CRP can foreshadow future cardiovascular problems.

But more recent research has some scientists guessing that CRP may be more than just a harbinger of disease.

Recently, researchers found that CRP could bind to Fc-gamma receptors on leukocytes or white blood cells. That means that "CRP will interact with the white cells and stimulate the production of a number of factors that are known to be inflammatory," Fisher explained. "Researchers have speculated that if this happens in the vessel wall, CRP can be a direct inflammatory molecule."

Earlier this year, researchers at the University of California, Davis (the same team that conducted this study) also found that CRP is produced by endothelial cells that line the artery walls (it was previously thought to be manufactured only by the liver).

Endothelial cells "are the critical cells that line the endothelial lining of coronary and cerebral arteries and participate in the first step of plaque formation," said Sridevi Devaraj, lead author of the current study and an associate professor of pathology. This brought CRP a little closer to the "ground zero" of heart disease, she said.

The question then became: How does CRP get into the endothelial cells?

"CRP promotes plaque formation so, obviously, the big question is 'How does it do this?'" Devaraj said. "It's a huge protein. Somehow it has to get into the cell."

This latest study, conducted by Devaraj and senior author Dr. Ishwarlal Jialal, showed that, in addition to binding to Fc-gamma receptors in white blood cells, CRP also binds to two members of the Fc-gamma receptor family found on endothelial cells.

And when those receptors were blocked with specific antibodies, CRP uptake was also blocked.

The key question for the future would be how to block CRP in the human body, although the scientists said they're still a long way from figuring that out.

These studies were conducted in the lab, and no one yet knows if the process works the same way in living, breathing people, Fisher said.

For one thing, it's not clear how CRP competes with the myriad other molecules that can also bind to Fc receptors. "What you don't know is how good is CRP at getting through the crowd of other things that will bind to Fc receptors and actually utilize this pathway?" Fisher said.

He cautioned that it is premature to draw any firm conclusions about these mechanisms. "Extrapolation at this point has to be somewhat limited," Fisher said. "No matter what we find in a cell model or in a mouse, what's going to trump all of that is what we find in people."

More information

The American Heart Association has more on CRP.