title: Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left ventricular geometry and function in mice.
abstract: Alterations in the expression and activity of the matrix metalloproteinases (MMPs) and the tissue inhibitors of the MMPs (TIMPs) have been implicated in tissue remodeling in a number of disease states. One of the better characterized TIMPs, TIMP-1, has been shown to bind to active MMPs and to regulate the MMP activational process. The goal of this study was to determine whether deletion of the TIMP-1 gene in mice, which in turn would remove TIMP-1 expression in LV myocardium, would produce time-dependent effects on LV geometry and function. Age-matched sibling mice (129Sv) deficient in the TIMP-1 gene (TIMP-1 knock-out (TIMP-1 KO), n=10) and wild-type mice (n=10) underwent comparative echocardiographic studies at 1 and 4 months of age. LV catheterization studies were performed at 4 months and the LV harvested for histomorphometric studies. LV end-diastolic volume and mass increased (18+/-4 and 38+/-3%, respectively, P<0.05) at 4 months in the TIMP-1 KO group; a significant increase compared to wild-type controls (P<0.05). At 4 months, LV and end-diastolic wall stress was increased by over two-fold in the TIMP-1 KO compared to wild type (P<0.05). However, LV systolic pressure and ejection performance were unchanged in the two groups of mice. LV myocyte cross-sectional area was unchanged in the TIMP-1 KO mice compared to controls, but myocardial fibrillar collagen content was reduced. Changes in LV geometry occurred in TIMP-1 deficient mice and these results suggest that constitutive TIMP-1 expression participates in the maintenance of normal LV myocardial structure.
authors.affiliation: Division of Cardiothoracic Surgery and Cardiology, Medical University of South Carolina and Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: L
authors.initials: L
authors.lastname: Roten
authors.forename: S
authors.initials: S
authors.lastname: Nemoto
authors.forename: J
authors.initials: J
authors.lastname: Simsic
authors.forename: M L
authors.initials: ML
authors.lastname: Coker
authors.forename: V
authors.initials: V
authors.lastname: Rao
authors.forename: S
authors.initials: S
authors.lastname: Baicu
authors.forename: G
authors.initials: G
authors.lastname: Defreyte
authors.forename: P J
authors.initials: PJ
authors.lastname: Soloway
authors.forename: M R
authors.initials: MR
authors.lastname: Zile
authors.forename: F G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D017353:Gene Deletion; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D051379:Mice; D018345:Mice, Knockout; D008867:Microtomy; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000502:physiology*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen