title: Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution.
abstract: BACKGROUND
  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.
  
  
  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; 0.5mg/kg/day) was delivered by osmotic mini-pump beginning 3h 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.
  
  
  CONCLUSIONS
  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.
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Rugmani Padmanabhan
authors: RP
authors: Iyer
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Nicolle L
authors: NL
authors: Patterson
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Fouad A
authors: FA
authors: Zouein
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Yonggang
authors: Y
authors: Ma
authors: Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines Bat, 152, CE-Saclay, Gif-sur-Yvette, France.
authors: Vincent
authors: V
authors: Dive
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: Lisandra E
authors: LE
authors: de Castro Brás
authors: San Antonio Cardiovascular Proteomics Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA. Electronic address: mllindsey@umc.edu.
authors: Merry L
authors: ML
authors: Lindsey
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000235:genetics*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D012313:RNA; D053508:Matrix Metalloproteinase 12
keywords: Apoptosis; CD44; LV remodeling; MMP-12; Neutrophil; Proteomics