Targeted overexpression of tissue inhibitor of matrix metalloproteinase-4 modifies post-myocardial infarction remodeling in mice

Circ Res. 2014 Apr 25;114(9):1435-45. doi: 10.1161/CIRCRESAHA.114.303634. Epub 2014 Mar 17.

Abstract

Rationale: 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.

Methods and 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.

Keywords: extracellular matrix; myocardial infarction; tissue inhibitor of metalloproteinases; ventricular function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Fibrillar Collagens / genetics
  • Fibrillar Collagens / metabolism
  • Gene Expression Regulation
  • Gene Targeting*
  • Gene Transfer Techniques*
  • Genetic Vectors
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Transgenic
  • Myocardial Infarction / genetics
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy*
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Recovery of Function
  • Stroke Volume
  • Time Factors
  • Tissue Inhibitor of Metalloproteinase-4
  • Tissue Inhibitor of Metalloproteinases / genetics
  • Tissue Inhibitor of Metalloproteinases / metabolism*
  • Ventricular Function, Left*
  • Ventricular Remodeling*

Substances

  • Cytokines
  • Fibrillar Collagens
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Tissue Inhibitor of Metalloproteinases
  • Green Fluorescent Proteins
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse