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). While LV ejection fraction (LVEF) fell in the WT-PO and TIMP-4 KO groups, LVEF was higher in the TIMP-4exp. LV Doppler revealed higher E/E' ratio with PO- indicative of abnormal diastolic filling patterns, and was lower in both the TIMP-4KO and TIMP-4exp groups. Collagen volume fraction (CVF) was increased with PO, but was reduced in the TIMP-4exp group.
Conclusions: These unique results directly demonstrated that changes in myocardial TIMP-4 alter both myocardial growth and matrix remodeling with a chronic pressure overload stimulus. These results underscore the pleotropic nature of TIMPs, such as TIMP-4 and challenge the canonical belief that TIMPs simply regulate matrix proteolysis in the context of LV remodeling.
- © 2010 by American Heart Association, Inc.