UCSF Researchers Identify Molecule Involved In Early Stage Of Atherosclerosis In Mice

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 proximal aortas. In contrast, mice lacking CCR2 had lesions that were nearly 50 percent smaller. In addition, markedly fewer macrophages, the cells that monocytes evolve into once they are in the vessel lining, were present in the aortas of these mice, demonstrating that activation of the receptor was important in the recruitment of monocytes into the vessel wall.

Co-authors of the UCSF study were Landin Boring, PhD, a postdoctoral fellow in the UCSF-affiliated Gladstone Institute of Cardiovascular Disease, Jennifa Gosling, MS, a research associate at the Gladstone and Michael Cleary, a research associate at the Gladstone. The study was funded by grants from the NIH and Gladstone Institute of Cardiovascular Disease.