Abstract 13228: Direct Modulation of Myocardial Tissue Inhibitor of Matrix Metalloproteinase-4 Alters the Course of Myocardial Growth and Matrix Remodeling with Pressure Overload

Background: Recent basic in vitro studies have identified that the tissue inhibitors of the matrix metalloproteinases (TIMPs), such as TIMP-4 which is highly expressed in the cardiovascular system, may regulate multiple biological pathways including myocardial growth as well as matrix remodeling. However, the direct effects of TIMP-4 with respect to LV remodeling in vivo and in a relevant pathophysiological context, remains unknown. This study tested the hypothesis that myocardial selective overexpression (TIMP-4exp) or targeted deletion (TIMP-4KO) would directly affect LV growth and matrix remodeling with pressure overload (PO). Methods/Results: PO (transverse aortic constriction) was induced in wild-type (WT; FVB n=15), TIMP-4exp (n=20; full length human TIMP-4), and TIMP-4KO (n=11) and results compared to non-PO WT (n=10; TABLE). At 4 weeks post-PO, LV mass increased in all groups, but was lower with TIMP-4exp and higher with TIMP-4KO, and was paralleled by changes in myocyte cross sectional area (CSA)...