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.
authors.affiliation: Department of Mechanical Engineering, The University of Texas at San Antonio, USA; Joint Biomedical Engineering Program, UTSA-UTHSCSA, USA; San Antonio Cardiovascular Proteomics Center, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Voorhees
authors.affiliation: San Antonio Cardiovascular Proteomics Center, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA.
authors.forename: Kristine Y
authors.initials: KY
authors.lastname: DeLeon-Pennell
authors.affiliation: San Antonio Cardiovascular Proteomics Center, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: San Antonio Cardiovascular Proteomics Center, USA; Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.affiliation: San Antonio Cardiovascular Proteomics Center, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
authors.affiliation: San Antonio Cardiovascular Proteomics Center, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA.
authors.forename: Rugmani Padmanabhan
authors.initials: RP
authors.lastname: Iyer
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Flynn
authors.affiliation: Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Cates
authors.affiliation: Joint Biomedical Engineering Program, UTSA-UTHSCSA, USA; San Antonio Cardiovascular Proteomics Center, USA; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, USA; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, USA.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: Department of Mechanical Engineering, The University of Texas at San Antonio, USA; Joint Biomedical Engineering Program, UTSA-UTHSCSA, USA; San Antonio Cardiovascular Proteomics Center, USA. Electronic address: hchan@utsa.edu.
authors.forename: Hai-Chao
authors.initials: HC
authors.lastname: Han
mesh_terms: D000818:Animals; D002306:Cardiac Volume; D003094:Collagen / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Cardiac mechanics; Collagen crosslinking; Infarct stiffness; Lysyl oxidase; Matrix metalloproteinase-9; Proteomics