The finding, published in the September 17 issue of the journal Circulation (available on the Web at http://www.circulationaha.org ), describes a new molecular pathway that stimulates plaque formation. The work is important because it provides a new target for drug development efforts, explains why cholesterol screening is not enough to accurately assess heart disease risk, and underscores the need to use c-reactive protein screening to more accurately assess at-risk populations.
In their series of experiments, UC Davis researchers found that c-reactive protein inhibits the activity of a very critical "protector" enzyme in the blood vessel wall. This protector enzyme, called eNOS, or endothelial nitric oxide synthase, produces nitric oxide, which works to keep blood vessels healthy and heart disease at bay by preventing plaques from adhering to blood vessel walls, keeping coronary arteries dilated and inhibiting constriction of smooth muscle cells.
At the molecular level, c-reactive protein decreases the stability of eNOS messenger RNA and prevents the activation of its second-messenger molecule, cyclic GMP. These events prevent eNOS from producing its protective biological effects. C-reactive protein also promotes white-blood-cell binding to blood vessel walls and stimulates the release of other adhesion molecules, including intercellular adhesion molecule 1, or 1CAM-1, and vascular cell adhesion molecule, or VCAM-1, which further promote plaque build-up.
"Without the protective effects of eNOS and the plaque-promoting effects of c-reactive protein, the blood vessel wall is ripe for the development of heart disease," said Ishwarlal Jialal, professor of pathology and director of the Laboratory for Athersclerosis and Metabolic Research at UC Davis School of Medicine and Medical Center. "The attachment of white blood cells and their entry into the vessel wall are early events that lead to fatty streaks or early plaque formation."
These novel findings at the molecular and cellular level support the work of other investigators who have shown that patients with increased levels of c-reactive protein have impaired blood vessel function, as measured by forearm blood flow. The findings also support current efforts to develop new screening guidelines.
"By using existing high-sensitive assays to measure c-reactive protein levels, we can better identify individuals who are truly at risk for heart disease and get them started on prescription drugs, lifestyle changes or other treatments as necessary to reduce these protein levels and to prevent disease," said Jialal, who is the Robert E. Stowell Endowed Chair in Experimental Pathology. "High risk groups include postmenopausal women and individuals with a positive family history of premature heart disease, hypertension, smoking or metabolic syndrome, a disorder characterized by a disproportionate amount of abdominal fat, elevated blood pressure, blood sugar and triglycerides and low levels of HDL, the "good" kind of cholesterol. Testing would be beneficial to individuals in these groups, especially when cholesterol levels are within the normal range and other risk factors and assessment measures indicate an intermediate level of risk for heart disease."
Other investigators at UC Davis contributing to this study include Sridevi Devaraj, assistant professor of pathology, and Senthil Venugopal, research fellow. Measures of eNOS enzymatic activity was performed in the laboratory of Philip Shaul, University of Texas Southwestern Medical Center at Dallas.
This research was supported with a grant from the National Institutes of Health.
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