Abstract 338: Matrix Metalloproteinase-14 Deletion from Bone Marrow-Derived Cells Induces Collagen Accumulation in Atherosclerotic Plaque
Interstitial collagen plays a crucial structural role in arteries. Membrane-bound Matrix metalloproteinase type 1 (MMP-14) may have collagenolytic activity, but its role in arterial collagen metabolism remains unknown. Mmp14−/ − mice have poor postnatal survival. Therefore, to test the hypothesis that Mmp-14 influences the structure of atheroma, this study used reconstitution of lethally irradiated low-density receptor-deficient mice (ldlr−/ −) with bone marrow cells from Mmp14−/ − or Mmp14+/+mice. Both groups consumed an atherogenic diet for 8 (n=17) or 16 weeks (n=12 and 14 respectively). Histological analyses of the aortic root of both groups revealed similar plaque size and content macrophages and smooth muscle cells accumulation after 8 and 16 weeks of atherogenic diet. However, by 16 weeks, the plaques of ldlr−/ − mice reconstituted with Mmp14−/ − bone marrow contained significantly more interstitial collagen than those of ldlr−/ − receiving Mmp14+/+bone marrow when we measured the percentage of positive area for picrosirius red staining into the intimal area (7.82 Â±4.4% and 3.29Â±2.81% respectively; P<0.05). In vitro collagenase assay with bone marrow-derived macrophages showed that Mmp14−/ − cells had significantly less collagenase activity than Mmp14+/+cells both with (P<0.01) and without (P<0.05) stimulation by TNFÃéÂ± Western blot analysis and gelatin zymography performed on aortic extract revealed that Mmp14 deficiency markedly decreased activation of MMP-13 but not MMP-2. These results establish a role for MMP-14 in regulation of the collagen content of mouse atherosclerotic plaques, a feature associated with plaque stability in humans.