From the Division of Cardiology, Emory University School of Medicine,
Atlanta, Ga.
Correspondence to Zorina S. Galis, PhD, Emory University School of Medicine, Division of Cardiology, 1639 Pierce Dr, WMB #319, Atlanta, GA 30322. E-mail zgalis{at}emory.edu
Background—Atherosclerotic plaque
destabilization triggers clinical cardiovascular
disease and thus represents an attractive therapeutic target.
Weakening of tissue through the action of matrix-degrading enzymes,
called matrix metalloproteinases (MMPs), released by resident
macrophages was previously implicated in unstable vascular
syndromes.
Methods and Results—We used a
hypercholesterolemic rabbit model of
atherosclerosis to investigate the
gelatinolytic activity associated with
macrophage-derived foam cells (FCs).
Gelatinolytic activity and expression of MMP-9 but
not of MMP-2 cosegregated with macrophage FCs in aortic
lesions. Macrophage-derived gelatinases were further
investigated in vitro. MMP-9 was identified as the main
macrophage-derived gelatinase in cells isolated from aortic
lesions and from granuloma induced in the same rabbits to increase cell
yield. Importantly, detection of activated MMP-9 in the FC
culture medium supports the notion that these cells can independently
initiate processing of secreted MMP zymogens to active enzymes. We
further examined whether FC gelatinolytic activity
is dependent on the presence of reactive oxygen species (ROS). We found
that treatment (1 to 5 days) with 1 to 10 mmol/L
N-acetyl-L-cysteine (NAC), an ROS scavenger,
decreased not only gelatinolytic activity but also
gelatinase expression by FCs. Similarly, NAC treatment of explanted
lesions abolished in situ gelatinolytic activity
and MMP-9 expression.
Conclusions—Macrophage FCs are an abundant source of
gelatinolytic activity that can be inhibited in
vitro and in situ by NAC. This newly described action of antioxidant
therapy might prove useful to inhibit matrix degradation and to improve
vascular stability.
© 1998 American Heart Association, Inc.
Basic Science Reports
N-Acetyl-Cysteine Decreases the Matrix-Degrading Capacity of Macrophage-Derived Foam Cells
New Target for Antioxidant Therapy?
Key Words: atherosclerosis • metalloproteinases • free radicals • antioxidants
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