Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 85, Issue -, Pages 229-239Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.06.006
Keywords
Cardiac mechanics; Collagen crosslinking; Matrix metalloproteinase-9; Lysyl oxidase; Infarct stiffness; Proteomics
Categories
Funding
- National Heart, Lung, and Blood Institute [HHSN 268201000036C (N01-HV-00244)]
- American Heart Association (AHA) [POST14350034, 14POST18770012]
- Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award [5I01BX000505]
- National Institutes of Health [K99-AT006704, R01HL075360, R01HL095852]
- NIH [HL051971, GM104357]
- NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE [K99AT006704] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL051971, R01HL095852, T32HL007446, R01HL075360] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM104357] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX000505] Funding Source: NIH RePORTER
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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