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

34 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 9
Dilatation
Collagen
Myocardial Infarction
Protein-Lysine 6-Oxidase
Heart Ventricles
Fibronectins
Bone Morphogenetic Protein 1
Metalloproteases
Cicatrix
Ligation
Coronary Vessels

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Building a better infarct : Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction. / Voorhees, Andrew P.; DeLeon-Pennell, Kristine Y.; Ma, Yonggang; Halade, Ganesh V.; Yabluchanskiy, Andriy; Iyer, Rugmani Padmanabhan; Flynn, Elizabeth; Cates, Courtney A.; Lindsey, Merry L; Han, Hai Chao.

In: Journal of Molecular and Cellular Cardiology, Vol. 85, 01.08.2015, p. 229-239.

Research output: Contribution to journalArticle

Voorhees, Andrew P. ; DeLeon-Pennell, Kristine Y. ; Ma, Yonggang ; Halade, Ganesh V. ; Yabluchanskiy, Andriy ; Iyer, Rugmani Padmanabhan ; Flynn, Elizabeth ; Cates, Courtney A. ; Lindsey, Merry L ; Han, Hai Chao. / Building a better infarct : Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction. In: Journal of Molecular and Cellular Cardiology. 2015 ; Vol. 85. pp. 229-239.
@article{e731167925eb491187ca7d60bf7b764c,
title = "Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction",
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.",
keywords = "Cardiac mechanics, Collagen crosslinking, Infarct stiffness, Lysyl oxidase, Matrix metalloproteinase-9, Proteomics",
author = "Voorhees, {Andrew P.} and DeLeon-Pennell, {Kristine Y.} and Yonggang Ma and Halade, {Ganesh V.} and Andriy Yabluchanskiy and Iyer, {Rugmani Padmanabhan} and Elizabeth Flynn and Cates, {Courtney A.} and Lindsey, {Merry L} and Han, {Hai Chao}",
year = "2015",
month = "8",
day = "1",
doi = "10.1016/j.yjmcc.2015.06.006",
language = "English (US)",
volume = "85",
pages = "229--239",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Building a better infarct

T2 - Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction

AU - Voorhees, Andrew P.

AU - DeLeon-Pennell, Kristine Y.

AU - Ma, Yonggang

AU - Halade, Ganesh V.

AU - Yabluchanskiy, Andriy

AU - Iyer, Rugmani Padmanabhan

AU - Flynn, Elizabeth

AU - Cates, Courtney A.

AU - Lindsey, Merry L

AU - Han, Hai Chao

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

KW - Cardiac mechanics

KW - Collagen crosslinking

KW - Infarct stiffness

KW - Lysyl oxidase

KW - Matrix metalloproteinase-9

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=84932650176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932650176&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2015.06.006

DO - 10.1016/j.yjmcc.2015.06.006

M3 - Article

VL - 85

SP - 229

EP - 239

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

ER -