Targeted Overexpression of Tissue Inhibitor of Matrix Metalloproteinase-4 Modifies Post–Myocardial Infarction Remodeling in Mice

• Published in: Circulation research Vol. 114; no. 9; pp. 1435 - 1445
• Main Authors: Zavadzkas, Juozas A, Stroud, Robert E, Bouges, Shenikqua, Mukherjee, Rupak, Jones, Jeffrey R, Patel, Risha K, McDermott, Paul J, Spinale, Francis G
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 25-04-2014
• Subjects: 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; Recombinant Fusion Proteins - metabolism; Recovery of Function; RNA, Messenger - metabolism; Stroke Volume; Time Factors; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases - genetics; Tissue Inhibitor of Metalloproteinases - metabolism; Ventricular Function, Left; Ventricular Remodeling; tissue inhibitor of metalloproteinases; extracellular matrix; myocardial infarction; ventricular function
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.114.303634

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 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.