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

Int J Cardiol. 2015 Apr 15:185:198-208. doi: 10.1016/j.ijcard.2015.03.054. Epub 2015 Mar 5.

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; 0.5mg/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.

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.

Keywords: Apoptosis; CD44; LV remodeling; MMP-12; Neutrophil; Proteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Immunoblotting
  • Immunohistochemistry
  • Inflammation / enzymology
  • Inflammation / genetics*
  • Male
  • Matrix Metalloproteinase 12 / biosynthesis
  • Matrix Metalloproteinase 12 / drug effects
  • Matrix Metalloproteinase 12 / genetics*
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Infarction / complications*
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / enzymology
  • RNA / genetics
  • Real-Time Polymerase Chain Reaction
  • Ventricular Dysfunction, Left / enzymology
  • Ventricular Dysfunction, Left / etiology
  • Ventricular Dysfunction, Left / genetics*
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology*
  • Ventricular Remodeling / physiology

Substances

  • Matrix Metalloproteinase Inhibitors
  • RNA
  • Matrix Metalloproteinase 12