Targeted Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-4 Modifies Post Myocardial Infarction Remodeling in Mice
Rationale: Myocardial infarction (MI) causes an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) and is associated with adverse LV remodeling. A uniform reduction in TIMP-4 post-MI has been observed.
Objective: 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, then randomized to targeted injection of an adenoviral construct (10 uL; 8X109 pfu/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 over 60% from baseline at 5 days post-MI and by over 100% at 21 days post-MI in the Ad-GFP only group. However, LV dilation was reduced by approximately 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-TIMP4 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 MMP inhibitors, such as TIMP-4, holds promise as a means to interrupt the progression of post-MI remodeling.
- matrix metalloproteinases
- myocardial infarction
- remodeling heart failure
- ventricular function
- extracellular matrix
- Received February 3, 2014.
- Revision received March 13, 2014.
- Accepted March 17, 2014.