Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction

Author:

Kandalam Vijay12,Basu Ratnadeep12,Abraham Thomas3,Wang Xiuhua12,Awad Ahmed12,Wang Wei42,Lopaschuk Gary D.42,Maeda Nobuyo5,Oudit Gavin Y.62,Kassiri Zamaneh12

Affiliation:

1. Department of Physiology,

2. Cardiovascular Research Center and The Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta;

3. James Hogg iCAPTURE Centre, University of British Columbia, Vancouver, British Columbia, Canada; and

4. Department of Pediatrics, and

5. University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

6. Department of Medicine/Division of Cardiology,

Abstract

Extracellular matrix (ECM) remodeling is a critical aspect of cardiac remodeling following myocardial infarction. Tissue inhibitors of metalloproteinases (TIMPs) are physiological inhibitors of matrix metalloproteinases (MMPs) that degrade the ECM proteins. TIMP3 is highly expressed in the heart, and is markedly downregulated in patients with ischemic cardiomyopathy. We therefore examined the time- and region-dependent role of TIMP3 in the cardiac response to myocardial infarction (MI). TIMP3−/− and wild-type (WT) mice were subjected to MI by ligation of the left anterior descending artery. TIMP3−/−-MI mice exhibited a significantly compromised rate of survival compared with WT-MI mice, primarily due to increased left ventricular (LV) rupture, greater infarct expansion, exacerbated LV dilation, and greater systolic and diastolic dysfunction. Second harmonic generation imaging of unfixed and unstained hearts revealed greater collagen disarray and reduced density in the TIMP3−/− infarct myocardium compared with the WT group. Gelatinolytic and collagenolytic activities increased in TIMP3−/− compared with WT hearts at 1 day post-MI but not at 3 days or 1 wk post-MI. Neutrophil infiltration and inflammatory MMPs were significantly increased in the infarct and peri-infarct regions of TIMP3−/−-MI hearts. Treatment of TIMP3−/− mice with a broad-spectrum MMP inhibitor (PD-166793) for 2 days before and 2 days after MI markedly improved post-MI infarct expansion, LV rupture incident, LV dilation, and systolic dysfunction in these mice up to 1 wk post-MI. Our data demonstrate that the initial rise in proteolytic activities early post-MI is a triggering factor for subsequent LV adverse remodeling, LV rupture, and dilated cardiomyopathy. Hence, timing of treatments to improve cardiac response to MI may be critical in producing favorable outcome.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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