For the first time, scientists have discovered how C-reactive protein, or CRP, is able to access endothelial cells. The UC Davis researchers' findings will be published in the July issue of Arteriosclerosis, Thrombosis, and Vascular Biology, one of the American Heart Association's leading journals.
CRP is a known risk marker for heart disease and, in a study published earlier this year, UC Davis researchers Ishwarlal Jialal and Sridevi Devaraj found that endothelial cells also produce CRP, which is increased 100-fold when cytokines are secreted by human macrophages, a key finding that helps to explain how plaque formation is initiated.
Devaraj and Jialal have now discovered how CRP affects endothelial cells, cells that line the cerebral and coronary arteries, and promotes plaque rupture, leading to heart attacks and strokes. CRP appears to bind to a family of immunoglobulin-processing receptors known as Fc-gamma receptors.
"In this study we convincingly show that CRP binds to two members of the Fc-gamma receptor family, CD64 and CD32, and that by blocking these receptors with specific antibodies, we can reverse the detrimental effects of CRP on endothelial cells," said Jialal, the Robert E. Stowell Chair of Experimental Pathology and director of the Laboratory of Atherosclerosis and Metabolic Research at UC Davis Medical Center.
"This is the first time that anyone has shown how CRP is able to get into the human aortic endothelial cells. Fc-gamma receptors CD32 and CD64 are the culprits," said Sridevi Devaraj, associate professor of pathology at UC Davis School of Medicine and Medical Center.
Work at UC Davis and other institutions has shown that CRP induces endothelial cell dysfunction, thus promoting plaque rupture. CRP 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, in a previous study, that CRP 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 CRP.
"In future studies, we will examine the precise pathways by which these receptors are able to mediate CRP effects so that more specific therapies can be developed to target inflammation," said Jialal.
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.
Reducing the concentration of CRP with drugs, such as statins, has been shown to reduce cardiovascular events. Treating other risk factors such as smoking, obesity, high blood pressure with angiotensin receptor blockers and diabetes with thiazolidinediones and metformin are also shown to reduce the levels of CRP.