Published online before print March 3, 2005, doi: 10.1161/01.ATV.0000161275.82687.f6
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Matrix Metalloproteinase-9 Modulation by Resident Arterial Cells Is Responsible for Injury-Induced Accelerated Atherosclerotic Plaque Development in Apolipoprotein E–Deficient Mice
From the Departments of Surgery (E.T. Choi, E.T. Collins, L.A.M., M.G.U., H.U., J.E.L., K.P.B.) and Internal Medicine (M.F.K., D.R.A.), Washington University School of Medicine, St. Louis, Mo; and the Department of Medicine (W.C.P.), University of Washington, Seattle.
Correspondence to Eric T. Choi, MD, Section of Vascular Surgery 660 S Euclid Ave, Campus Box 8109 St. Louis, MO 63110. E-mail choie{at}msnotes.wustl.edu
Objective— Although matrix metalloproteinase-9 (MMP-9) has been implicated in atherosclerotic plaque instability, the exact role it plays in the plaque development and progression remains largely unknown. We generated apolipoprotein E (apoE)–deficient (apoE–/–) MMP-9–deficient (MMP-9–/–) mice to determine the mechanisms and the main cell source of MMP-9 responsible for the plaque composition during accelerated atherosclerotic plaque formation.
Methods and Results— Three weeks after temporary carotid artery ligation revealed that while on a Western-type diet, apoE–/– MMP-9–/– mice had a significant reduction in intimal plaque length and volume compared with apoE–/– MMP-9+/+ mice. The reduction in plaque volume correlated with a significantly lower number of intraplaque cells of resident cells and bone marrow–derived cells. To determine the cellular origin of MMP-9 in plaque development, bone marrow transplantation after total-body irradiation was performed with apoE–/– MMP-9+/+ and apoE–/– MMP-9–/– mice, which showed that only MMP-9 derived from resident arterial cells is required for plaque development.
Conclusions— MMP-9 is derived from resident arterial cells and is required for early atherosclerotic plaque development and cellular accumulation in apoE–/– mice.
We studied the role of MMP-9 in rapid atherosclerotic plaque development in a mouse model. Compared with apoE–/– MMP-9+/+ mice, plaque volume and cellular accumulation were significantly reduced in apoE–/– MMP-9–/– mice. Furthermore, plaque burden is intimately linked to MMP-9 generated by resident arterial cells and not the bone marrow–derived cells.
Key Words: atherosclerosis • MMP-9 • bone marrow • mouse • compartmentalization
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