This Article Full Text Full Text (PDF) All Versions of this Article: 117/7/931    most recent CIRCULATIONAHA.107.707448v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Schneider, F. Articles by Libby, P. PubMed PubMed Citation Articles by Schneider, F. Articles by Libby, P. Related Collections Acute coronary syndromes Other Vascular biology Animal models of human disease Cell biology/structural biology Related Article

(Circulation. 2008;117:931-939.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques

Fabrice Schneider, MD; Galina K. Sukhova, PhD; Masanori Aikawa, MD, PhD; James Canner, MA; Norbert Gerdes, PhD; Sai-Man Timothy Tang, Bsc; Guo-Ping Shi, DSc; Suneel S. Apte, MBBS, DPhil; Peter Libby, MD

From the Donald W. Reynolds Cardiovascular Clinical Research Center and Fondation Leducq Transatlantic Network on Atherothrombosis (F.S., G.K.S., M.A., J.C., N.G., S.-M.T.T., G.-P.S., P.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Service de Chirurgie Vasculaire (F.S.), Hôpital Henri Mondor, Créteil, France; Department of Biomedical Engineering (S.S.A.), Lerner Research Institute Cleveland Clinic, Cleveland, Ohio; and Center for Molecular Medicine (N.G.), Karolinska Institute, Stockholm, Sweden.

Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB 741, Boston, MA 02115. E-mail plibby{at}rics bwh.harvard.edu

Received April 29, 2007; accepted November 27, 2007.

Background— Interstitial collagen plays a crucial structural role in arteries. Although in vitro results suggest collagenase activity for membrane-bound matrix metalloproteinase type 1 (MMP-14), in vivo evidence for such a function in atherosclerosis remains scant.

Methods and Results— Because Mmp14^–/– mice die by 3 weeks of age, this study used lethally irradiated low-density lipoprotein receptor–deficient mice reconstituted with syngeneic bone marrow cells of Mmp14^–/– or Mmp14^+/+ mice. In both groups, histological analyses of the aortic root revealed similar plaque size and macrophage and smooth muscle cell content after 8 or 16 weeks of atherogenic diet. By 16 weeks, however, the plaques of low-density lipoprotein receptor–deficient mice engrafted with Mmp14^–/– bone marrow (n=12) contained significantly more interstitial collagen than those receiving Mmp14^+/+ bone marrow (n=14; P<0.05). In vitro, bone marrow–derived macrophages from Mmp14^–/– mice had significantly less interstitial collagenase activity than those from Mmp14^+/+ mice both basally (P<0.01) and on tumor necrosis factor- stimulation (P<0.05). Western blot analysis and gelatin zymography of aortic extracts revealed that MMP-14 deficiency yielded decreased activation of pro–MMP-13 but not of pro–MMP-2 or pro–MMP-8.

Conclusion— MMP-14 from bone marrow–derived cells can influence the collagen content of mouse atheroma, a critical component of plaque stability.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 857-859. [Full Text]