Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution

Rugmani Padmanabhan Iyer, Nicolle L. Patterson, Fouad A. Zouein, Yonggang Ma, Vincent Dive, Lisandra E. De Castro Brás, Merry L. Lindsey

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Rationale Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. Objective The goal was to determine MMP-12 post-MI mechanisms. Methods and results Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5 mg/kg/day) was delivered by osmotic mini-pump beginning 3 h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n = 6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 ± 1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. Conclusion Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.

Original languageEnglish (US)
Pages (from-to)198-208
Number of pages11
JournalInternational Journal of Cardiology
Volume185
DOIs
StatePublished - Apr 15 2015

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Matrix Metalloproteinase 12
Myocardial Infarction
Inflammation
Matrix Metalloproteinases
Neutrophils
Hyaluronic Acid
Caspase 3
Heart Ventricles
Apoptosis
Interleukin-11
Ventricular Remodeling
Matrix Metalloproteinase Inhibitors
Caspase 8
Atherosclerotic Plaques
Inbred C57BL Mouse

Keywords

  • Apoptosis
  • CD44
  • LV remodeling
  • MMP-12
  • Neutrophil
  • Proteomics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution. / Iyer, Rugmani Padmanabhan; Patterson, Nicolle L.; Zouein, Fouad A.; Ma, Yonggang; Dive, Vincent; De Castro Brás, Lisandra E.; Lindsey, Merry L.

In: International Journal of Cardiology, Vol. 185, 15.04.2015, p. 198-208.

Research output: Contribution to journalArticle

Iyer, Rugmani Padmanabhan ; Patterson, Nicolle L. ; Zouein, Fouad A. ; Ma, Yonggang ; Dive, Vincent ; De Castro Brás, Lisandra E. ; Lindsey, Merry L. / Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution. In: International Journal of Cardiology. 2015 ; Vol. 185. pp. 198-208.
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AU - Iyer, Rugmani Padmanabhan

AU - Patterson, Nicolle L.

AU - Zouein, Fouad A.

AU - Ma, Yonggang

AU - Dive, Vincent

AU - De Castro Brás, Lisandra E.

AU - Lindsey, Merry L.

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N2 - Rationale Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. Objective The goal was to determine MMP-12 post-MI mechanisms. Methods and results Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5 mg/kg/day) was delivered by osmotic mini-pump beginning 3 h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n = 6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 ± 1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. Conclusion Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.

AB - Rationale Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. Objective The goal was to determine MMP-12 post-MI mechanisms. Methods and results Male C57BL/6J mice (3-6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5 mg/kg/day) was delivered by osmotic mini-pump beginning 3 h post-MI, and mice were sacrificed at day (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n = 6-12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33 ± 1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. Conclusion Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.

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