Abstract 1280: The Pericellular Collagenase MT1-MMP Regulates Post-Infarction Ventricular Remodeling and Cardiac Function
Cardiac extracellular matrix contains an intricate network of fibrillar type I collagen essential for cardiac structure and function. Secreted matrix metalloproteinases (MMPs) degrade type I collagen and have been postulated to regulate matrix remodeling after myocardial infarction. However, mice deficient in the major collagenolytic MMPs display only modest improvements in survival and cardiac function after infarction, raising the possibility that the major proteinase responsible for cardiac remodeling has not yet been identified. The membrane-bound matrix metalloproteinase, MT1-MMP, expresses collagenolytic activity and is the dominant collage-nase in mesenchymal cells. Accordingly, we hypothesized that MT1-MMP would be an important mediator of post-infarct cardiac function and remodeling.
Methods and Results-Cardiovascular remodeling and function were examined in MT1-MMP+/+ (n=24) and MT1-MMP+/− (n=20) mice after left coronary artery ligation. MT1-MMP+/− mice had significantly better survival compared to MT1-MMP+/+ mice (78 vs 46%, p<0.05). MT1-MMP+/− mice also had less LV dilatation (diastolic dimension 4.26±0.2 vs 4.68±0.1 mm, p=0.05), better contractility (ejection fraction 70±5 vs 63±5%, p<0.05) and better diastolic function (mitral annular tissue velocity E/A 1.0±0.1 vs 0.8±0.2, p<0.05) by echocardiography compared to MT1-MMP+/+ mice at 28 days post infarct. Infarct size (31±5 vs 39±4%, p±0.05) and cardiomyocyte hypertrophy (myocyte area 269±34 vs 334±52 μm2, p<0.05) were significantly reduced in MT1-MMP+/− mice. MT1-MMP+/− mice also displayed a significant increase in collagen area fraction (0.87±0.06 vs 0.76±0.05%, p<0.05) and type I collagen expression within the matrix of infarcted tissue despite comparable levels of MMP-2 and MMP-9 relative to MT1-MMP+/+ mice. Apoptotic index and vascular density were similar between groups.
Conclusions-Reduced MT1-MMP levels are associated with improved survival and significant alterations in cardiac remodeling and function after infarction. Mice with reduced MT1-MMP expression provide a new model for defining collagen-integrin-cytoskeletal-myofibril interactions in the heart, and reveal a useful therapeutic strategy to modify post-infarct remodeling.