C-reactive protein is a risk marker for heart disease and is known to be produced in the liver, but UC Davis School of Medicine researchers Ishwarlal Jialal and Sridevi Devaraj found that endothelial cells also produce C-reactive protein, a key finding that helps to explain how plaque formation is initiated. This is particularly important because endothelial cells are supposed to protect the arteries from C-reactive protein.
"This is an extremely important finding," says Jialal, professor of pathology and internal medicine and director of the Laboratory for Atherosclerosis and Metabolic Research at UC Davis Medical Center. "We have convincingly demonstrated in this paper that aortic and coronary artery endothelial cells produce and secrete C-reactive protein. We also showed within the artery, mature white cells, called macrophages, make chemical messengers, cytokines, which enhance the C-reactive protein secretion by endothelial cells at least 10-fold.
"This tells us that there is cross-talk in the active plaque where these cells act in concert to cause very high C-reactive protein levels in the atheroma, which is the accumulation of plaque on the innermost layer of the artery," Jialal said. "The C-reactive protein produced by endothelial cells can not only act on the endothelial cells, but also on macrophages and smooth muscle cells in the atheroma. This creates a vicious cycle, leading to plaque instability and rupture, and ultimately heart attacks and strokes."
Work at UC Davis and other institutions has shown that C-reactive protein induces endothelial cell dysfunction, thus promoting plaque formation. C-reactive protein causes endothelial cells to produce less nitric oxide and to increase the number of cell adhesion molecules. This, in turn, allows damaging leukocytes to enter the vessels. Devaraj and Jialal also showed that C-reactive protein induces endothelial cells to produce plasminogen activator inhibitor, or PAI-1, which promotes clot formation. In addition, recent studies suggest that plaque tissue also produces C-reactive protein.
Coronary heart disease is the nation's single leading cause of death. According to the American Heart Association, approximately 1.2 million Americans will have a coronary attack this year. Almost a half million of these people will die. About 7.1 million Americans have survived a heart attack. And another 6.4 million Americans have experienced chest pain or discomfort due to reduced blood supply to the heart.
The good news is that reducing the concentration of C-reactive protein with targeted drugs, such as statins, has been shown to reduce cardiovascular events. Treating other risk factors such as smoking, obesity, high blood pressure and high cholesterol are also shown to reduce the levels of C-reactive protein.
Senthil Kumar Venugopal, a postgraduate researcher in the Laboratory of Atherosclerosis and Metabolic Research participated in the study.
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