Macrophage Cells Fail to Remove the Fatty Deposits, and Weill Cornell Team May Now Know Why
NEW YORK (August 8, 2007) – Scientists at Weill Cornell Medical College in New York City have gotten closer to solving a longstanding puzzle in cardiovascular medicine: Why immune scavenger cells called macrophages fail to complete their job of ridding blood vessels of dangerous cholesterol plaques.
It now appears that the very act of interacting with low-density lipoprotein (LDL or "bad") cholesterol alters the macrophage's ability to move away from the vessel wall. The result is an accumulation of macrophages that contain so much cholesterol that they become swollen "foam cells."
"In our experiments in the laboratory, we discovered that increases in membrane cholesterol levels, like those that may occur when cells interact with LDL, interfere with key signaling mechanisms within the macrophage – signaling that would otherwise 'tell' it to take its cholesterol load and migrate away from the vessel," explains co-senior author Dr. Lynda Pierini, assistant professor of microbiology and immunology in the department of surgery at Weill Cornell Medical College.
Her team just published its findings in the American Heart Association's journal Arteriosclerosis, Thrombosis, and Vascular Biology, where it was highlighted on the journal's cover.
"We are extremely pleased with the journal's decision to emphasize the importance of this work. The mystery of why macrophages fail to remove cholesterol from blood vessels is an enduring one in medicine, but we believe these findings go a long way to clearing up that mystery," says co-senior author Dr. Frederick Maxfield, Israel Rogosin Professor of Biochemistry and chair of the department of biochemistry at Weill Cornell.
As millions of heart patients know all too well, cholesterol buildup is a prime cause of high blood pressure, heart attack and stroke. But the body's immune system does have a built-in method of clearing away LDL plaque and transporting it to the liver for disposal.
"The cells involved in this process are called macrophages. Unfortunately, they appear to be only capable of doing half of their job," Dr. Pierini explains.
The macrophages are attracted to LDL cholesterol lying within blood vessels, and they do go to work scooping up these dangerous fats.
But then they get stuck.
"They don't move away from the vessel as they should. Instead, they remain along the vessel wall, swollen with cholesterol until they become foam cells. In that way, they end up becoming part of the atherosclerotic problem," Dr. Pierini explains.
In this and a prior study (also published in ATVB), her team used precise laboratory experiments to determine just what was going wrong.
They discovered that increases in the macrophages' membrane cholesterol levels inhibit the activation of what's known as the RhoA/Rho kinase signaling pathway within the cell.
"This pathway is a biochemical regulator that the macrophage uses to say, 'OK, it's time now to move out of the blood vessel wall,'" Dr. Maxfied explains. However, in a variety of experiments, it became clear to the team that increases in membrane cholesterol block that signaling.
"In fact, there's a significant drop in levels of active RhoA enzyme in cholesterol-heavy macrophages, and these cells tend to spread out and just sit there rather than migrate," he said.
It's likely that cholesterol loading affects other biochemical mechanisms that could disrupt macrophage migration, the researchers stress. However, its inhibition of the RhoA/Rho kinase pathway is likely to remain key.
While the finding doesn't have immediate implications for anti-cholesterol drug research, it could point to new pharmaceutical targets down the line, the researchers say.
"Certainly, this might help explain why statin medications are so good at reducing plaque build-up," Dr. Pierini notes. "It's speculative, but statins might help limit the amount of cholesterol that gets into macrophage cell membranes and promote macrophage regression from plaques, for example. It is certainly our hope that as we gain a better understanding of these cholesterolemic processes, it will end up helping patients."
This research was funded by the U.S. National Institutes of Health.
Co-researchers include lead author Dr. Tomokazu Nagao, Dr. Chunbo Qin and Dr. Inna Grosheva – all of the Department of Biochemistry at Weill Cornell Medical College.
Weill Cornell Medical College
Weill Cornell Medical College – Cornell University's Medical School located in New York City – is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, AIDS, obesity, cancer, psychiatry and public health – and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College – in its commitment to global health and education – has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Salzburg, and Turkey. With the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances – from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient.
Andrew Klein
ank2017@med.cornell.edu