Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice

Abstract

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1−/− mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1−/− mice demonstrated that LV end-diastolic volume [52 ± 4 (WT) vs. 71 ± 6 (TIMP-1−/−) μl] and LV end-diastolic pressure [9.0 ± 1.2 (WT) vs. 12.7 ± 1.4 (TIMP-1−/−) mmHg] were significantly increased in the TIMP-1−/− mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1−/− groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1−/− mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1−/−controls may have been an important contributory factor for the observed LV alterations in the TIMP-1−/− mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1.