Journal
CIRCULATION
Volume 117, Issue 7, Pages 931-939Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.107.707448
Keywords
atherosclerosis; collagen; metalloproteinases; pathology; plaque
Funding
- NHLBI NIH HHS [R01 HL080472, HL-080472] Funding Source: Medline
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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-alpha 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.
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