Abstract 13288: An Oral Inhibitor Of Matrix Metalloproteinase 13 (MMP-13) Increases Collagen Content Of Mouse Atheromata
Introduction: Rupture of atherosclerotic plaques in coronary arteries causes many fatal acute myocardial infarctions. Interstitial collagen lends tensile strength to the fibrous cap, and our previous data implicate MMP-13 in plaque collagenolysis.
Hypothesis & Methods: To test the hypothesis that oral administration of a selective MMP-13 inhibitor (MMP13i-A) increases collagen accumulation in plaques, this study used atherosclerosis-susceptible apoE deficient mice with nascent or established lesions (n≥10). Macrophage accumulation and MMP-13 inhibition by MMP13i-A compound in vivo were assessed by molecular imaging and collagen content by picrosirius red birefringence.
Results: MMP13i-A inhibited MMP-13 but no other proteinases tested in vitro. Both recombinant MMP-13 as well as supernatants from stimulated human and murine macrophages showed reduced MMP-13 activity after incubation with MMP13i-A. Treatment of MMP13i-A for 10 weeks significantly reduced MMP-13 activity assessed by both intravital microscopy and Fluorescence Reflectance Imaging (p<0.01) using a near infrared MMP-13 activatable fluorescent probe and macrophage-phagocytosable fluorescent nanoparticles. In contrast, this treatment did not affect macrophage phagocytic activity, plaque size and smooth muscle cell accumulation. Consistent with the imaging results, the content of macrophages did not differ between treated and controls animals. MMP13i-A treatment on either nascent or already established atheromata significantly increased interstitial collagen content as compared to vehicle treated mice (8.1±1.1% vs 13.9±1.7%; p< 0.01 and 22.2±1.4% vs 30.7±1.9%; p<0.001). Furthermore, qualitative analysis revealed thicker intimal collagen fibers within the plaques of treated groups. MMP13i-A did not affect expression of MMP-8,-14,-2,-12 or Cathepsin K in lesions indicating a lack of compensatory alterations in these proteases due to MMP-13 inhibition in vivo.
Conclusion: These data indicate that pharmacologic MMP-13 inhibition yields collagen accumulation in plaque, a feature associated in humans with resistance to rupture. This study also validates molecular imaging strategies to study plaque biology in vivo.
- © 2010 by American Heart Association, Inc.