Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice
Esther E J M Creemers, Jeniffer N Davis, Andrea M Parkhurst, Peter Leenders, Kathryn B Dowdy, Elizabeth Hapke, Anne M Hauet, Patricia G Escobar, Jack P M Cleutjens, Jos F M Smits, Mat J A P Daemen, Michael R Zile, Francis G Spinale, Esther E J M Creemers, Jeniffer N Davis, Andrea M Parkhurst, Peter Leenders, Kathryn B Dowdy, Elizabeth Hapke, Anne M Hauet, Patricia G Escobar, Jack P M Cleutjens, Jos F M Smits, Mat J A P Daemen, Michael R Zile, Francis G Spinale
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(-/-)) microl] 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.
Source: PubMed