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Macrophage function in atherosclerosis

Institution: Scripps Research Institute
Investigator(s): Linda Curtiss, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0161 Award: $709,200
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Atherosclerosis is a disease that eventually blocks blood flow in arteries. When this occurs in the heart, it leads to a heart attack. Although a heart attack occurs rapidly, the events that lead up to this acute event, begin very early in life. Early atherosclerotic disease changes are seen in young adults and even infants. Tobacco use makes this disease progress even faster. In fact, the effect of current cigarette smoking is essentially equivalent to an additional two decades of aging.

Cigarette smoke goes to the lungs and from there into the bloodstream. Components in tobacco smoke are toxic to the cells called endothelial cells) that cover and protect the inside of the arteries. When injured these endothelial cells make and release small molecules that alert other cells in the blood that something is wrong. These other blood cells (called macrophages) become sticky and attach to the endothelial cells. Eventually, these macrophages move between and under the endothelial cells into an area of the artery called the intima. This event, the entry and accumulation of macrophages into the intima of the wall of the artery, is the first stage of atherosclerotic disease. This stage is reversible if the macrophages do their job to repair the artery and leave. However, with repeated injuries to the artery, such as those that occur in people who smoke every day, the macrophages remain in the intima and recruit more macrophages. To do this, they too make and release small molecules (called chemokines) that let the circulating macrophages know there is continued artery injury. As additional macrophages enter the intima, the wall of the artery gets thicker. It becomes so big that it can be seen with the naked eye. At this point it is called a complicated atherosclerotic plaque. Over time, the intima can become so thick that the inner layer of endothelial cells breaks apart. Once this happens, blood flow is obstructed and a heart attack occurs.

Our laboratory has discovered that macrophages that do not have a specific protein receptor on their surface (called CXCR2) do not remain in the intima of the artery. Atherosclerosis-prone mice that are genetically deficient in this receptor have macrophages that enter the vessel wall, but for some reason the cells do not stay there and no disease progression occurs in these deficient mice. We need to know how in normal animals, macrophages with this CXCR2 receptor remain in the intima and promote formation of an advanced complicated plaque that can rupture and block blood flow. We will study artery entry and retention of macrophages into the intima. We will test a number of hypotheses to explain this macrophage retention. For example, this macrophage CXCR2 receptor may allow the macrophage to survive, to divide and grow, to become stickier, to be less active, or to make and secrete other molecules that prevent repair. When we know what macrophages with this CXCR2 receptor actually do to promote disease progression, we will know how to design or engineer a drug that will prevent this macrophage receptor from making atherosclerosis get worse. With this information we can help all people with atherosclerosis so they do not get the complicated atherosclerotic plaques that lead to a heart attack.

Participation of innate and acquired immunity in atherosclerosis
Periodical: Immunologic Research Index Medicus:
Authors: Curtiss LK, Kubo N, Schiller NK, Boisvert WA ART
Yr: 2000 Vol: 21 Nbr: Abs: Pg: 167-176