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(Circulation. 2005;112:2708-2715.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic Plaques

Jun-O Deguchi, MD, PhD; Elena Aikawa, MD, PhD; Peter Libby, MD; Jeffrey R. Vachon, BS; Masaki Inada, DDSci, PhD; Stephen M. Krane, MD; Peter Whittaker, PhD; Masanori Aikawa, MD, PhD

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (J.D., E.A., P.L., J.R.V., M.A.); Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass (M.I., S.M.K.); and Departments of Emergency Medicine and Anesthesiology, University of Massachusetts Medical School, Worcester (P.W.).

Correspondence to Masanori Aikawa, MD, PhD, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 741, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu

Received May 13, 2005; revision received July 8, 2005; accepted July 20, 2005.

Background— Interstitial collagen plays a crucial structural role in arteries. Matrix metalloproteinases (MMPs), including MMP-13/collagenase-3, likely contribute to collagen catabolism in atherosclerotic plaques.

Methods and Results— To test the hypothesis that a specific MMP-collagenase influences the development and structure of atherosclerotic plaques, this study used atherosclerosis-susceptible apolipoprotein E–deficient mice that lack MMP-13/collagenase-3 (Mmp-13^–/–/apoE^–/–) or express wild-type MMP-13/collagenase-3 (Mmp-13^+/+/apoE^–/–). Both groups consumed an atherogenic diet for 5 (n=8) or 10 weeks (n=9). Histological analyses of the aortic root of both groups revealed similar plaque size and accumulation of smooth muscle cells (a collagen-producing cell type) and macrophages (a major source of plaque collagenases) after 5 and 10 weeks of atherogenic diet. By 10 weeks, the plaques of Mmp-13^–/–/apoE^–/– mice contained significantly more interstitial collagen than those of Mmp-13^+/+/apoE^–/– mice (P<0.01). Furthermore, quantitative optical analyses revealed thinner and less aligned periluminal collagen fibers within the plaques of Mmp-13^+/+/apoE^–/– mice versus those from Mmp-13^–/–/apoE^–/– mice.

Conclusions— These data support the hypothesis that MMP-13/collagenase-3 plays a vital role in the regulation and organization of collagen in atherosclerotic plaques.

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