title: Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice.
abstract: BACKGROUND
  Myocardial infarction (MI) causes an imbalance between matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases (TIMPs) and is associated with adverse left ventricular (LV) remodeling. A uniform reduction in TIMP-4 post-MI has been observed.
  
  
  OBJECTIVE
  To examine post-MI remodeling with cardiac-restricted overexpression of TIMP-4, either through a transgenic or viral delivery approach.
  
  
  RESULTS
  MI was induced in mice and then randomized to targeted injection of an adenoviral construct (10 μL; 8×10(9) plaque forming units/mL) encoding green fluorescent protein (GFP) and the full-length human TIMP-4 (Ad-GFP-TIMP4) or GFP. A transgenic construct with cardiac-restricted overexpression TIMP-4 (hTIMP-4exp) was used in a parallel set of studies. LV end-diastolic volume, an index of LV remodeling, increased by >60% from baseline at 5 days post-MI and by >100% at 21 days post-MI in the Ad-GFP only group. However, LV dilation was reduced by ≈50% in both the Ad-GFP-TIMP4 and hTIMP-4exp groups at these post-MI time points. LV ejection fraction was improved with either Ad-GFP-TIMP-4 or hTIMP-4exp. Fibrillar collagen expression and content were increased within the MI region with both TIMP-4 interventions, suggestive of matrix stabilization.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that selective myocardial targeting for TIMP-4 induction through either a viral or transgenic approach favorably altered the course of adverse LV remodeling post-MI. Thus, localized induction of endogenous matrix metalloproteinase inhibitors, such as TIMP-4, holds promise as a means to interrupt the progression of post-MI remodeling.
authors.affiliation: From the Department of Surgery (J.A.Z., R.E.S., S.B., R.M., J.R.J., R.K.P.), and Department of Medicine (P.J.M.), Medical University of South Carolina, Charleston; Ralph H. Johnson Veteran's Affairs Medical Center, Charleston, SC (J.A.Z., R.E.S., S.B., R.M., J.R.J., R.K.P., P.J.M.); Department of Cell Biology & Anatomy and Surgery, University of South Carolina School of Medicine, Columbia (F.G.S.); and WJB Dorn VA Medical Center, Columbia, SC (F.G.S.).
authors.forename: Juozas A
authors.initials: JA
authors.lastname: Zavadzkas
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Shenikqua
authors.initials: S
authors.lastname: Bouges
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jones
authors.forename: Risha K
authors.initials: RK
authors.lastname: Patel
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McDermott
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D024022:Fibrillar Collagens / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020127:Recovery of Function; D013318:Stroke Volume; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D016207:Cytokines; D024022:Fibrillar Collagens; D049452:Green Fluorescent Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse
keywords: extracellular matrix; myocardial infarction; tissue inhibitor of metalloproteinases; ventricular function