Building a Better Infarct: Modulation of Collagen Cross-Linking to Increase Infarct Stiffness and Reduce Left Ventricular Dilation Post-Myocardial Infarction
Cardiac mechanics, Collagen crosslinking, Infarct stiffness, Lysyl oxidase, Matrix metalloproteinase-9, Proteomics
Digital Object Identifier (DOI)
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.
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Citation / Publisher Attribution
Journal of Molecular and Cellular Cardiology, v. 85, p. 229-239
This article is the post-print author version. Final version available at: https://doi.org/10.1016/j.yjmcc.2015.06.006
Scholar Commons Citation
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.; and Han, Hai Chao, "Building a Better Infarct: Modulation of Collagen Cross-Linking to Increase Infarct Stiffness and Reduce Left Ventricular Dilation Post-Myocardial Infarction" (2015). Internal Medicine Faculty Publications. 43.