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Impaired cell cleanup associated with abdominal aortic aneurysms, new study finds

Abdominal aortic aneurysms may be caused by the overexpression of a "don't eat me" protein that blocks the disposal of dead and dying cells.

Research has shown that when the body loses its ability to get rid of dead cells bad things can happen — like cancer or atherosclerosis.

Now, a new Stanford study shows that a kink in the dead cell garbage disposal system plays a role in the development of abdominal aortic aneurysms, a leading killer of older men.

“This discovery could possibly provide a powerful way to prevent aneurysms from enlarging,” said Nicholas Leeper, MD, senior author of the study that appears in Circulation.

An abdominal aortic aneurysm is defined as a dilation of the lower part of the aorta, the major blood vessel in the body. Because the aorta is the body's main supplier of blood, a ruptured abdominal aortic aneurysm can cause life-threatening bleeding into the abdomen. Currently, there is no non-surgical treatment to prevent a aneurysm rupture. It’s often described as having a “time bomb” in your abdomen.

This study builds on previous research by Irving Weissman, MD, professor of pathology and developmental biology at Stanford and a co-author on this study. Weissman and colleagues first identified an overexpression of the protein CD47 in tumor cells. This protein sits on surfaces of certain cells sending out the signal “don’t eat me” to the body, meaning that the cell is still healthy and should not be thrown out.

Normally, as a cell approaches death, CD47 starts to disappear, allowing immune cells called macrophages to take out the dying cell. In the case of some tumors, its overexpression was shown to prevent destruction of cancerous cells. Researchers showed that by blocking CD47, they restored the macrophages ability to take out the garbage.

In an earlier study, Leeper and colleagues showed that a similar process — the inappropriate expression of CD47 — contributes to the buildup of plaque in artery walls causing atherosclerosis, another deadly heart disease and the leading cause of death worldwide.

“We think that reactivating the clearance of these diseased and dying and dead cells is really important in atherosclerosis,” Leeper said. “By inducing the clearance all that debris we can shrink the plaque.”

In this new study, spearheaded by research scientist Yoko Kojima, MD, PhD, researchers tested aortic aneurysm tissue samples from humans and also found increased levels of CD47. They then gave mice with these aneurysms the anti-CD47 antibodies, and found that they developed significantly smaller aortic diameters, a positive development.

On further investigation, researchers determined that in this case, it wasn’t that macrophages were now getting rid of all those dead cells and debris, but the fact that they were also allowed to do their second job, which is to release anti-inflammatory factors that benefit the vessel walls.

“In an aneurysm, macrophages that are not able to do their job seem to become frustrated,” Leeper said. “They get inflamed and secrete inflammatory cytokines [molecules] that can promote degeneration or dilation of the vessel wall... So in this case, we’re taking advantage of anti-inflammatory factors and preventing the production of factors that hasten aneurysm rupture."

In the future, the blockade of CD47, which is currently in human trials for patients with advanced solid tumors or lymphoma, could also be investigated as a new therapy for aortic aneurysms, if the human studies prove to be safe, the study said.

Image by cocoparisienne

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