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April 26, 2002



Understanding Complex Roles of MMP Enzymes in the Arterial Wall Could Lead to Therapies Preventing Heart Attack and Stroke

NEW ORLEANS— An Emory University scientist who pioneered the hypothesis that enzymes called matrix metalloproteinases (MMPs) play an important role in the structural failure that leads to heart attack and stroke will describe recent results of her work at the Experimental Biology '02 meeting in New Orleans. Zorina Galis, Ph.D., associate professor of medicine and biomedical engineering at Emory University School of Medicine, will speak on Wednesday, April 24, and chair part of the symposium entitled "New developments in vascular biology and inflammation."

"The clinical consequences of atherosclerosis, or hardening of the arteries, continue to kill more people than the next seven major causes of death combined, including cancer and HIV," says Dr. Galis. Recently scientists have learned that the sequence of events leading to myocardial infarction (heart attack) and stroke begins with weakening of the arterial tissue, followed by destabilization of atherosclerotic plaques, which contain cholesterol and lipids that build up during the life of an artery. When these plaques become unstable and rupture, thrombosis (clotting), results, ultimately leading to blockage of the blood flow. Dr. Galis has pioneered the hypothesis that MMPs enable this step-wise process by breaking down the scaffolding, called the extracellular matrix, that shapes and stabilizes arteries.

"Understanding the complex roles of MMPs in the arterial wall is essential for developing effective and safe therapies and for the tissue engineering approaches to treat or replace diseased blood vessels," Dr. Galis says.

Research highlights by Dr. Galis and her colleagues at the Experimental Biology meeting:
  • Atherosclerotic Lesions Grow By Recruiting Circulating Inflammatory Cells, Which Multiply Within Arteries
    Atherosclerotic plaques become increasingly prone to structural failure as they gain a growing number of inflammatory cells. This structural breakdown is the cause of acute cardiovascular events such as heart attack and stroke. Through an Established Investigator Award from the American Heart Association, Dr. Galis has developed an experimental model of genetically engineered mice to study how atherosclerotic plaque forms. Through different kinds of cell surface markers, she can distinguish between circulating inflammatory cells and those already present in the arterial wall. Using this model, Dr. Galis and her colleagues, post-doctoral fellow Susan Lessner, Emory undergraduate Heather Prado and collaborator Dr. Ned Waller, have demonstrated that atherosclerotic plaques recruit circulating inflammatory cells, and that once these cells join the plaque, they multiply and contribute to the growth of the plaque. This knowledge could lead to drug-based strategies aimed at blocking the infiltration of inflammatory cells in the early stages of atherosclerotic plaque formation and blocking the proliferation of inflammatory cells in more mature plaques.

  • (MMP)-9 Enzymes Enable Cells to Migrate Within Arteries and Attach to Extracellular Matrix
    Newly discovered functions of MMP enzymes show that they play both beneficial and harmful roles. As blood vessels and arteries develop and repair, MMPs help cells break down and reorganize or "remodel" their matrix — the complex molecular scaffold that gives arteries structural support by holding cells together. The remodeling process controlled by MMPs can be either beneficial or deleterious based on location, timing, or extent. Dr. Galis presents evidence showing that enzymes known to degrade the extracellular matrix are also essential in putting the molecules back together. For example, the same MMP-driven process of releasing the matrix barriers that initially allow an artery to enlarge in the face of a growing atherosclerotic plaque also ends up weakening the artery and creating the opportunity for a heart attack. As part of the Georgia Tech-Emory tissue engineering center funded by the National Science Foundation, Dr. Galis and graduate student Chad Johnson have discovered that MMP-9 enzymes are important in helping cells break off and migrate through the matrix proteins, and that MMP-9 enzymes with a genetic defect make it harder for these cells to migrate. They believe limiting the migration of vascular cells may be an effective therapy to limit the growth of arterial plaques that occur naturally during atherosclerosis, or during restenosis following surgical interventions aimed at widening diseased arteries.

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