MMP
ENZYMES PLAY KEY ROLE IN STABILITY AND BREAKDOWN OF ATHEROSCLEROTIC
PLAQUES
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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