title: 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: 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 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE (n = 38), TIMP-4KO (n = 24), as well as age/strain-matched wild type (WT, n = 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 ~25% lower in the TIMP-4KO group (P < 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 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups (P < 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.
authors.affiliation: Sisters of Charity Providence Hospitals, Columbia, South Carolina.
authors.forename: William M
authors.initials: WM
authors.lastname: Yarbrough
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Catalin
authors.initials: C
authors.lastname: Baicu
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: An
authors.initials: A
authors.lastname: Van Laer
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: William T
authors.initials: WT
authors.lastname: Rivers
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Richard A
authors.initials: RA
authors.lastname: McKinney
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Corey B
authors.initials: CB
authors.lastname: Prescott
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.affiliation: University of South Carolina School of Medicine, WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina;
authors.forename: Parker D
authors.initials: PD
authors.lastname: Freels
authors.affiliation: University of South Carolina School of Medicine, WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina;
authors.forename: Kia N
authors.initials: KN
authors.lastname: Zellars
authors.affiliation: Division of Cardiothoracic Surgery and Adult Cardiology, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina; and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.affiliation: University of South Carolina School of Medicine, WJB Dorn Veterans Affairs Medical Center, Columbia, South Carolina; cvctrc@uscmed.sc.edu.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D017353:Gene Deletion; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
keywords: pressure-overload hypertrophy; remodeling; tissue inhibitors of metalloproteinase