© 1997 American Heart Association, Inc.
Articles |
Thrombin Promotes Activation of Matrix Metalloproteinase-2 Produced by Cultured Vascular Smooth Muscle Cells
From the Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Boston, Mass (R.K., P.L.); Emory University School of Medicine, Cardiology Division, Atlanta, Ga (Z.S.G.); and the Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany (J.W.F.).
Abstract Thrombin generated at sites of vascular injury not
only participates in the coagulation cascade but can signal other
events related to development and complication of atherosclerotic
plaques. We investigated here a novel nonthrombotic action of thrombin:
the possibility that this protease influences the expression or
activation of matrix metalloproteinases (MMPs) produced by vascular
smooth muscle cells (SMCs). Matrix-degrading proteinases likely
contribute to several aspects of vascular lesion development. Vascular
SMCs constitutively elaborate the zymogen form of gelatinase A (MMP-2),
found in cell supernatants complexed with its inhibitor, the tissue
inhibitor of metalloproteinases (TIMP)-2. When activated, MMP-2 digests
collagens and elastin and may thus promote cell migration and vascular
remodeling. Analysis of culture supernatants harvested from either
human or rabbit vascular SMCs by gelatin zymography revealed that
compared with supernatants of unstimulated SMCs, media conditioned by
thrombin-stimulated cells contained increased amounts of
proteolytically processed MMP-2, suggesting activation of this MMP.
Further experiments tested whether thrombin directly activates MMP-2.
In cell-free experiments, when added to medium harvested from
unstimulated SMCs, 
-thrombin increased in a dose- and time-dependent
manner the amount of proteolytically processed MMP-2, as shown by
zymography and by Western blotting with specific antibodies. Thrombin
cleaved pro–MMP-2 within 4 hours, even when the gelatinase was bound
with its inhibitor, TIMP-2. Thrombin treatment rendered culture media
of unstimulated SMCs able to degrade collagen type IV, consistent with
generation of active MMP-2. Addition of inhibitors of either thrombin
or MMPs decreased this type IV collagenolytic activity, but thrombin in
the absence of SMC-conditioned medium containing pro–MMP-2 exhibited
only minimal collagenolysis. Our results suggest that at sites of
vascular injury, thrombin may activate locally produced MMP-2 and
thereby facilitate cell migration and proliferation. In the case of
complicated atherosclerotic plaques, episodes of intraplaque hemorrhage
or plaque disruption with thrombosis may promote plaque instability by
increasing local matrix-degrading activity.
Key Words: thrombin • metalloproteinases • atherosclerosis • vascular remodeling • tissue repair
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|
|
|
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|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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