Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice.
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.
Creemers
Esther E J M
EE
Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands.
Davis
Jeniffer N
JN
Parkhurst
Andrea M
AM
Leenders
Peter
P
Dowdy
Kathryn B
KB
Hapke
Elizabeth
E
Hauet
Anne M
AM
Escobar
Patricia G
PG
Cleutjens
Jack P M
JP
Smits
Jos F M
JF
Daemen
Mat J A P
MJ
Zile
Michael R
MR
Spinale
Francis G
FG
D000818:Animals; D004452:Echocardiography; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009203:Myocardial Infarction / Q000503:physiopathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000502:physiology*
D019715:Tissue Inhibitor of Metalloproteinase-1