Building a Better Infarct: Modulation of Collagen Cross-Linking to Increase Infarct Stiffness and Reduce Left Ventricular Dilation Post-Myocardial Infarction

Andrew P. Voorhees, Kristine Y. DeLeon-Pennell, Yonggang Ma, Ganesh V. Halade, Andriy Yabluchanskiy, Rugmani Padmanabhan Iyer, Elizabeth Flynn, Courtney A. Cates, Merry L. Lindsey, Hai Chao Han

Research output: Contribution to journalArticlepeer-review

Abstract

Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood.The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n = 88) and MMP-9 null (MMP-9-/-; n = 92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n = 42). At day 7 post-MI, WT LVs displayed a 3-fold increase in end-diastolic volume, while MMP-9-/- showed only a 2-fold increase (p < 0.05). Biaxial mechanical testing revealed that MMP-9-/- infarcts were stiffer than WT infarcts, as indicated by a 1.3-fold reduction in predicted in vivo circumferential stretch (p < 0.05). Paradoxically, MMP-9-/- infarcts had a 1.8-fold reduction in collagen deposition (p < 0.05). This apparent contradiction was explained by a 3.1-fold increase in lysyl oxidase (p < 0.05) in MMP-9-/- infarcts, indicating that MMP-9 deletion increased collagen cross-linking activity. Furthermore, MMP-9 deletion led to a 3.0-fold increase in bone morphogenetic protein-1, the metalloproteinase that cleaves pro-collagen and pro-lysyl oxidase (p < 0.05) and reduced fibronectin fragmentation by 49% (p < 0.05) to enhance lysyl oxidase activity. We conclude that MMP-9 deletion increases infarct stiffness and prevents LV dilation by reducing collagen degradation and facilitating collagen assembly and cross-linking through preservation of the fibronectin network and activation of lysyl oxidase.

Original languageAmerican English
JournalJournal of Molecular and Cellular Cardiology
Volume85
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Keywords

  • Cardiac mechanics
  • Collagen crosslinking
  • Infarct stiffness
  • Lysyl oxidase
  • Matrix metalloproteinase-9
  • Proteomics

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