期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 100, 期 -, 页码 109-117出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.10.005
关键词
MMP-9; Proteomics; Neutrophil; Apoptosis; Myocardial infarction; Macrophage; Inhibitor
资金
- American Heart Association [14POST18770012, 14SDG18860050]
- NIH HHSN [268201000036C (N01-HV-00244), HL075360, HL129823, HL051971, GM104357, GM114833, CA098799]
- Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award [5I01BX000505]
Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6 months old, n = 116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03 mu g/day) treatment was initiated at 3 h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 31 +/- 1% at D1 post-MI (p < 0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p < 0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice. (C) 2016 Elsevier Ltd. All rights reserved.
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