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 journalArticle

39 Scopus citations

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 languageEnglish (US)
Pages (from-to)229-239
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume85
DOIs
StatePublished - Aug 1 2015

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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