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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1647.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Low Tissue Inhibitor of Metalloproteinases 3 and High Matrix Metalloproteinase 14 Levels Defines a Subpopulation of Highly Invasive Foam-Cell Macrophages

Jason L. Johnson; Graciela B. Sala-Newby; Yasmin Ismail; Concepción M. Aguilera; Andrew C. Newby

From the Bristol Heart Institute, University of Bristol, England. Current address for C.M.A.: Department of Biochemistry and Molecular Biology, Institute of Nutrition and Food Technology, University of Granada, Spain.

Correspondence to Jason Lee Johnson, Bristol Heart Institute, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, England. E-mail jason.l.johnson{at}bristol.ac.uk

Objective— An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo.

Methods and Results— In vivo generated rabbit FCM exhibited 84% reduced TIMP-3 protein compared to nonfoamy macrophages, and immunocytochemistry revealed a TIMP-3 negative subset (28%). Strikingly, only TIMP-3 negative FCM invaded a synthetic basement membrane, and invasion was inhibited by exogenous TIMP-3. TIMP-3 negative FCM also had increased proliferation and apoptosis rates compared to TIMP-3 positive cells, which were retarded by exogenous TIMP-3; this also reduced gelatinolytic activity. TIMP-3 negative FCM were found at the base of advanced rabbit plaques and in the rupture-prone shoulders of human plaques. To explain the actions of low TIMP-3 we observed a 26-fold increase in MT1-MMP (MMP-14) protein in FCM. Adding an MT1-MMP neutralizing antibody reduced foam-cell invasion, apoptosis, and gelatinolytic activity. Furthermore, MT1-MMP overexpressing and TIMP-3 negative FCM were found at the same locations in atherosclerotic plaques.

Conclusions— These results demonstrate that TIMP-3 is downregulated in a distinct subpopulation of FCM which have increased MMP-14. These cells are highly invasive and have increased proliferation and apoptosis, all properties expected to destabilise atherosclerotic plaques.

We report here that a subset of rabbit foam-cell macrophages exhibits reduced TIMP-3/MT1-MMP balance and is highly invasive, proliferative, and prone to undergo apoptosis, characteristics associated with plaque instability. Foam-cell macrophages lacking TIMP-3 and overexpressing MMP-14 were also identified in advanced human plaques, underlying their potential proatherogenic role.

Key Words: atherosclerosis • tissue inhibitors of matrix metalloproteinases • macrophages • foam cells • plaque vulnerability

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