|
By MITZI BAKER The first lecture in this year’s Translational Research Program seminar series at the Beckman Center focused on a new molecule that may be able to predict the risk of cardiovascular disease. Presented by John Cooke, MD, PhD, professor of cardiovascular medicine, the research builds upon advances from the laboratory of Richard Zare, PhD, the Marguerite Blake Wilbur Professor in Natural Science in the department of chemistry. A postdoctoral scholar in Zare’s lab, Gabriele Trapp, PhD, successfully separated blood products that may make Cooke’s work directly apply to human patients. Before he provided the details of this risk-predicting molecule, Cooke offered a backgrounder on the endothelium, a single-cell lining of blood vessels that exerts control over cardiovascular function. If the endothelium is exposed to unhealthy conditions, such as high cholesterol, high glucose and tobacco byproducts, it generates characteristic changes that promote vascular disease. These changes are mediated by a number of factors, one of which is a molecule called asymmetric dimethylarginine, or ADMA. High levels of ADMA are a link in the chain that may lead to systemwide cardiovascular damage. "We think that this is one common mechanism by which traditional risk factors impair endothelial function and lead to disease," said Cooke. Through a sequence of reactions in the endothelium, ADMA plays a critical role in the cardiovascular system via its regulation of a molecule called nitric oxide, or NO. A combination of nitrogen and oxygen, NO is a small gaseous molecule that can easily penetrate cell membranes, playing a role in numerous biological processes. In relation to heart health, NO relaxes and dilates blood vessels and it helps prevent hardening of the arteries, by preventing platelets and white blood cells from sticking to the vessel wall. Also, NO can reduce the production of free radicals, high-energy compounds that can cause cellular damage — known as oxidative stress — over time if they aren’t removed. Cooke said that for every risk factor that they have studied in cardiovascular disease, including glucose levels, blood pressure, cholesterol and homocysteine, all of them increase levels of oxidative stress in blood vessels. A chain of events is initiated by oxidative stress that results in ADMA levels being increased, thus interfering with NO’s ability to function in maintaining healthy blood vessels. NO is a very short-lived molecule, lasting only seconds in the blood, so Cooke reasoned that ADMA could provide a more stable marker for testing the extent of the vessel-damaging process. Trapp provided the bench aspect of the ADMA bench-to-bedside collaboration. ADMA is difficult to measure in the blood, Trapp said, but necessary to test Cooke’s hypotheses about it being a marker for cardiovascular risk in humans. For months, Trapp tested different separation strategies, and has devised a method involving a fluorescent dye attached to the molecule. Her approach has achieved 95 percent accuracy. Now that the test has been optimized, researchers must analyze 3,000 blood samples Cooke has collected from patients in a collaboration with Kaiser Permanente. Over 15 years, Kaiser patients have donated samples for the study. Once the Stanford group determines the ADMA levels in each patients’ blood, it may become clear whether high levels are associated with coronary events, such as heart attacks. "By analyzing all these samples, we are going to determine if a high ADMA level truly is an independent and valuable risk factor," said Cooke.
|
Event to show cardiac controversy (4/25/02)
Arterial disorder vastly under diagnosed, may increase other health
risks (10/31/01)
|
Stanford Report, November 19, 2003
