Matrix Metalloproteinase-13 Predominates Over Matrix Metalloproteinase-8 as the Functional Interstitial Collagenase in Mouse Atheromata

Abstract

Objective— Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics. Approach and Results— Apolipoprotein E–deficient (apoE −/− ) mice, MMP-13 −/− apoE −/− , MMP-8 −/− apoE −/− double knockout mice, and MMP-13 −/− MMP-8 −/− apoE −/− triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE −/− controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13–deficient and MMP-13–deficient mice accumulate more fibrillar collagen than apoE −/− controls and MMP-8 −/− apoE −/− double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells. Conclusions— These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.