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

Vijay Kandalam, Ratnadeep Basu, Thomas Abraham, Xiuhua Wang, Ahmed Awad, Wei Wang, Gary D. Lopaschuk, Nobuyo Maeda, Gavin Y. Oudit, Zamaneh Kassiri

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)H1012-H1023
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number4
DOIs
StatePublished - Oct 1 2010

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Matrix Metalloproteinases
Myocardial Infarction
Rupture
Matrix Metalloproteinase Inhibitors
Dilatation
Tissue Inhibitor of Metalloproteinases
Ventricular Remodeling
Neutrophil Infiltration
Extracellular Matrix Proteins
Dilated Cardiomyopathy
Cardiomyopathies
Extracellular Matrix
Ligation
Myocardium
Collagen
Down-Regulation
Survival Rate
Arteries

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kandalam, Vijay ; Basu, Ratnadeep ; Abraham, Thomas ; Wang, Xiuhua ; Awad, Ahmed ; Wang, Wei ; Lopaschuk, Gary D. ; Maeda, Nobuyo ; Oudit, Gavin Y. ; Kassiri, Zamaneh. / Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 4. pp. H1012-H1023.
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Early activation of matrix metalloproteinases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction. / Kandalam, Vijay; Basu, Ratnadeep; Abraham, Thomas; Wang, Xiuhua; Awad, Ahmed; Wang, Wei; Lopaschuk, Gary D.; Maeda, Nobuyo; Oudit, Gavin Y.; Kassiri, Zamaneh.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 4, 01.10.2010, p. H1012-H1023.

Research output: Contribution to journalArticle

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AU - Kandalam, Vijay

AU - Basu, Ratnadeep

AU - Abraham, Thomas

AU - Wang, Xiuhua

AU - Awad, Ahmed

AU - Wang, Wei

AU - Lopaschuk, Gary D.

AU - Maeda, Nobuyo

AU - Oudit, Gavin Y.

AU - Kassiri, Zamaneh

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N2 - 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.

AB - 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.

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