From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular
Division, Department of Medicine, Brigham and Women's Hospital, Harvard
Medical School (M.A., E.R., Y.O., S.J.V., G.K.S., P.L.), and the Department of
Medicine, Dana-Farber Cancer Institute, Harvard Medical School (S.K.C.),
Boston, Mass; and the Department of Medicine, Dartmouth Medical School
(C.E.B.), Hanover, NH.
Correspondence to Dr Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background—Proteolytic enzyme
activity in lipid-rich atheroma may promote plaque rupture
and precipitate acute coronary syndromes. This study tested the
hypothesis that lipid lowering stabilizes plaques by reducing
proteolytic activity.
Methods and Results—We produced experimental atheroma
in 33 rabbits by balloon injury and an atherogenic diet (0.3%
cholesterol and 4.7% coconut oil) for 4 months. At that
time, 15 rabbits were killed (baseline group). The remaining animals
were divided into two groups: a hyperlipemic group continued to consume
a cholesterol-enriched diet (0.05% to 0.2%) for 16 more
months (n=5) and a lipid-lowering group consumed a purified chow diet
with no added cholesterol or fat for 8 (n=3) or 16 months
(n=10). Macrophage accumulation and interstitial
collagenase (matrix metalloproteinase-1, MMP-1) expression
in the lesion were measured by quantitative image analysis of
standardized sections of immunostained aortas. Baseline
lesions expressed high levels of MMP-1 and contained many
macrophages. These features of plaque instability persisted in
the hyperlipemic group. However, the lipid-lowering group showed
progressive reduction in both macrophage content and MMP-1
immunoreactivity with time. Aortic rings of the baseline and
hyperlipemic groups elaborated gelatinolytic,
caseinolytic, and elastinolytic activity attributable to MMP-2, MMP-3,
or MMP-9, monitored by SDS-PAGE zymography. Proteolytic activity
decreased markedly in the lipid-lowering group. Aortic content of
interstitial collagen, determined by sirius red staining,
increased in the lipid-lowering group compared with the baseline or
continued hyperlipemic groups, indicating that lipid lowering
reinforced the fibrous skeleton of the atheroma.
Conclusions—These results establish a mechanism by which lipid
lowering may stabilize vulnerable plaques by reduced expression and
activity of enzymes that degrade the arterial extracellular
matrix and render atheroma less susceptible to disruption
and thrombosis by favoring collagen accumulation in the fibrous cap.
© 1998 American Heart Association, Inc.
Basic Science Reports
Lipid Lowering by Diet Reduces Matrix Metalloproteinase Activity and Increases Collagen Content of Rabbit Atheroma
A Potential Mechanism of Lesion Stabilization
Key Words: metalloproteinases • atherosclerosis • diet • hypercholesterolemia • collagen
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