Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction.
Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction.
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DOI：
10.1016/j.yjmcc.2012.07.017
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发表时间：
2012-11
影响因子：
5
通讯作者：
Lindsey ML
中科院分区：
文献类型：
--
作者：
Zamilpa R;Ibarra J;de Castro Brás LE;Ramirez TA;Nguyen N;Halade GV;Zhang J;Dai Q;Dayah T;Chiao YA;Lowell W;Ahuja SS;D'Armiento J;Jin YF;Lindsey ML
心肌梗死(MI)后，活化的巨噬细胞作为强大的促炎反应的一部分渗入坏死的心肌中，并分泌基质金属蛋白酶-9(MMP9)。巨噬细胞的激活反过来又通过刺激成纤维细胞细胞外基质(ECM)的合成来调节纤维化反应。我们假设，在小鼠巨噬细胞中过表达人基质金属蛋白酶-9会放大炎症和纤维化反应，从而加剧左心功能不全。出乎意料的是，在心肌梗死后第5天，转基因(TG)小鼠的射血分数(25±2%)比野生型(WT)小鼠(18±2%；p<；0.05)有所改善。通过基因表达谱分析，与WT组小鼠相比，TG组的84个炎症基因中有23个在左室梗死(LVI)区域减少(均P<；0.05)。同时，从LVI分离的TG巨噬细胞和经内毒素刺激的TG腹膜巨噬细胞与WT巨噬细胞相比，炎症标志物的表达降低。与炎症减轻相一致的是，与西药组相比，TGLVI组84个细胞黏附和ECM基因中只有7个增加，而43个基因减少(均P<；0.05)。这些结果揭示了巨噬细胞来源的基质金属蛋白酶-9在钝化炎症反应和限制细胞外基质合成以改善心肌梗死后左心功能方面的新作用。
Following myocardial infarction (MI), activated macrophages infiltrate into the necrotic myocardium as part of a robust pro-inflammatory response and secrete matrix metalloproteinase-9 (MMP-9). Macrophage activation, in turn, modulates the fibrotic response, in part by stimulating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of human MMP-9 in mouse macrophages would amplify the inflammatory and fibrotic responses to exacerbate left ventricular dysfunction. Unexpectedly, at day 5 post-MI, ejection fraction was improved in transgenic (TG) mice (25±2%) compared to the wild type (WT) mice (18±2%; p<0.05). By gene expression profiling, 23 of 84 inflammatory genes were decreased in the left ventricle infarct (LVI) region from the TG compared to WT mice (all p<0.05). Concomitantly, TG macrophages isolated from the LVI, as well as TG peritoneal macrophages stimulated with LPS, showed decreased inflammatory marker expression compared to WT macrophages. In agreement with attenuated inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG LVI compared to WT LVI, while 43 genes were decreased (all p<0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and limiting ECM synthesis to improve left ventricular function post-MI.
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DOI：
10.1152/ajplung.00042.2009
发表时间：
2010-02-01
影响因子：
4.9
作者：
Mehra, Divya;Sternberg, David I.;D'Armiento, Jeanine
通讯作者：
D'Armiento, Jeanine
影响因子：
6.1
作者：
Tao, ZY;Cavasin, MA;Yang, XP
通讯作者：
Yang, XP
影响因子：
37.8
作者：
Nahrendorf M;Pittet MJ;Swirski FK
通讯作者：
Swirski FK
影响因子：
2.2
作者：
Thompson, JL;Ryan, JA;Schwarz, MA
通讯作者：
Schwarz, MA
DOI：
10.1126/science.1175202
发表时间：
2009-07-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Swirski FK;Nahrendorf M;Etzrodt M;Wildgruber M;Cortez-Retamozo V;Panizzi P;Figueiredo JL;Kohler RH;Chudnovskiy A;Waterman P;Aikawa E;Mempel TR;Libby P;Weissleder R;Pittet MJ
通讯作者：
Pittet MJ