New Predictor Of Heart Disease Risk Found: Damage Caused By Block Of Critical Protector Protein In Blood Cell Wall

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Source:   University Of California, - Medical Center

(http://www.ucdmc.ucdavis.edu)

Date:   Posted 8/27/2002

New Predictor Of Heart Disease Risk Found: Damage Caused By Block Of

Critical " Protector " Protein In Blood Cell Wall

SACRAMENTO, Calif. -- Cardiovascular research is increasingly showing that a

new predictor of heart disease risk, c-reactive protein, is just as

important as monitoring cholesterol levels to prevent and treat heart

disease and other ills, including stroke, sudden death and peripheral

vascular disease. Now, UC physicians have discovered that this protein

is not just a marker for heart disease, but that it actually damages the

blood vessel wall by blocking a critical " protector " protein and by

promoting plaque formation.

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 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

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 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 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.