title: Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload.
abstract: BACKGROUND
  Although matrix metalloproteinases (MMPs) were initially thought to result primarily in extracellular matrix degradation, certain MMP types, such as membrane type-1 (MT1) MMP, may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor-binding protein (LTBP-1) and activation of transforming growth factor-dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus.
  
  
  RESULTS
  Wild-type (WT) and transgenic mice with cardiac-restricted MT1-MMP overexpression or MT1-MMP reduced expression underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass/volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP-mediated LTBP-1 hydrolysis and a 190% increase in collagen content in WT mice. Although LV mass was similar among WT, MT1-MMP overexpression, and MT1-MMP reduced expression after PO, significant differences in LV function, MT1-MMP-mediated LTBP-1 hydrolysis, and collagen content occurred. PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and left atrial dimension (19%; indicative of LV diastolic dysfunction) when compared with WT. PO in MT1-MMP reduced expression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when compared with both WT.
  
  
  CONCLUSIONS
  Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix-dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to PO.
authors.affiliation: Division of Cardiology, Department of Medicine and Division of Cardiothoracic Surgery, Department of Surgery, R.H. Johnson Department of Veterans Affairs Medical Center, Medical University of South Carolina, Charleston; and W.J.B. Dorn Department of Veterans Affairs Medical Center, University of South Carolina School of Medicine, Columbia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zile
authors.forename: Catalin F
authors.initials: CF
authors.lastname: Baicu
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: An O
authors.initials: AO
authors.lastname: Van Laer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
authors.forename: Risha
authors.initials: R
authors.lastname: Patel
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D005786:Gene Expression Regulation; D017379:Hypertrophy, Left Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D015151:Immunoblotting; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D017725:Ventricular Pressure / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D012313:RNA; D053511:Matrix Metalloproteinase 14
keywords: hypertrophy; left ventricular; matrix metalloproteinases