UC San Francisco researchers have demonstrated in genetically engineered mice that a molecule known as MCP-1 plays a key role in promoting the migration of white blood cells into the lining of arteries, an event that ultimately leads to atherosclerosis.
The finding, reported in the August 27 issue of Nature, provides evidence that MCP-1 is critically involved in the formation of foam cell-laden fatty streaks, a hallmark of atherosclerosis, according to the senior author of the study, Israel F. Charo, MD, PhD, associate director of the UCSF-affiliated Gladstone Institute of Cardiovascular Disease, and a professor of medicine at UCSF.
"We've identified a mechanism whereby oxidized lipids attract monocytes to the vessel wall," said Charo.
"This should encourage pharmaceutical companies to ramp up their efforts to find an antagonist for this receptor."
Researchers have long known that the movement of monocytes, a type of white blood cell, into artery walls is an early step in the development of atherosclerosis. And cell culture studies have provided strong evidence that MCP-1 (monocyte chemoattractant protein-1) is a powerful attractant for monocytes. Significantly, synthesis of MCP-1 in blood vessel wall cells, such as endothelial cells, is upregulated by oxidized lipids.
The Gladstone researchers set out to determine whether MCP-1 was, in fact, the molecular lynch pin between the oxidized lipids resulting from a high-fat diet and the migration of monocytes into the artery wall.
Charo's team examined the outcomes in two sets of mice that were genetically engineered to be highly susceptible to atherosclerosis. One group of mice was also missing the receptor (CCR2) for MCP-1 on monoctyes that allows MCP-1 to have an effect. Both groups of mice were fed a western-type, high-fat diet for five to 13 weeks and then analyzed for signs of atherosclerosis.
The results were dramatic. The first group of mice developed robust lesions on
their prox
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Contact: Jennifer O'Brien
jobrien@itsa.ucsf.edu
(415) 476-2557
University of California - San Francisco
26-Aug-1998