Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy

Abstract

MR, Spinale FG. Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 307: H752-H761, 2014. First published July 3, 2014; doi:10.1152/ajpheart.00063.2014.-Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 Ϯ 0.1 mo of age, equal sex distribution) with TIMP-4OE (n ϭ 38), TIMP-4KO (n ϭ 24), as well as age/strain-matched wild type (WT, n ϭ 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ϳ25% lower in the TIMP-4KO group (P Ͻ 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 Ϯ 2% and 45 Ϯ 3%, respectively) but was higher with TIMP-4OE (57 Ϯ 2%, P Ͻ 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups (P Ͻ 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.remodeling; tissue inhibitors of metalloproteinase; pressure-overload hypertrophy LEFT VENTRICULAR (LV) pressure overload (LVPO), which occurs secondary to aortic valve stenosis and/or systemic hypertension, causes myocyte hypertrophy and abnormal extracellular matrix (ECM) accumulation. While both of these cellular and extracellular processes represent crucial events in the progression of LVPO, past studies have demonstrated that the progressive changes in both the content and structure of the ECM secondary to LVPO directly affect LV function and clinical outcomes (2,3,8,18,22,31). One pathway that contributes to ECM content and turnover is the expression and activation of the matrix metalloproteinases (MMPs), and the relationship to the endogenous tissue inhibitors of MMPs (TIMPs) (5-7, 27). TIMPs were initially identified to bind to active MMPs, and hence these small-molecular-weight proteins w...

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