Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution.
Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution.
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DOI：
10.1016/j.ijcard.2015.03.054
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发表时间：
2015-04-15
影响因子：
3.5
通讯作者：
Lindsey ML
中科院分区：
文献类型：
--
作者：
Iyer RP;Patterson NL;Zouein FA;Ma Y;Dive V;de Castro Brás LE;Lindsey ML
基质金属蛋白酶（MMPs）调节心肌梗死（MI）后左心室（LV）重构。MMP-12在动脉粥样硬化斑块中具有强有力的巨噬细胞依赖性重塑特性;然而，MI后的作用尚未研究。目的是确定MI后MMP-12的机制。对雄性C57 BL/6 J小鼠（3-6月龄）进行左冠状动脉结扎。从MI后3小时开始，通过渗透性微型泵递送盐水或RXP 470.1 MMP-12抑制剂（MMP-12 i; 0.5 mg/kg/天），并在MI后第1、3、5或7天（d）处死小鼠，并与d 0对照（无MI的小鼠; n=6-12/组/时间）进行比较。MMP-12表达增加MI后早期，与预期相反，中性粒细胞是MMP-12的一个令人惊讶的早期细胞来源。在MI后第1天，MMP-12 i使MMP-12活性降低33±1%。尽管梗死面积和存活率相似，但MMP-12 i导致更大的LV扩张和LV功能恶化。在MI后第7天，MMP-12 i延长了促炎细胞因子（IL 1 r1、IL 6 ra、IL 11和Cxcr 5）的上调，并降低了CD 44（基因和蛋白水平）。HA（一种CD 44配体）在MI后第1天和第7天与MMP 12 i一起升高，这是碎片减少的结果。由于CD 44-HA调节中性粒细胞清除，因此评价了凋亡标志物。MMP-12 i组心肌梗死后第7天caspase 3水平升高，而裂解caspase 3水平降低，表明中性粒细胞凋亡减少。在分离的中性粒细胞中，活性MMP-12直接刺激CD 44、caspase 3和caspase 8的表达。我们的研究结果揭示了MMP-12在中性粒细胞生物学中的一种新的保护机制。MI后，MMP-12 i损害CD 44-HA相互作用以抑制中性粒细胞凋亡并延长炎症，这使LV功能恶化。
Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined. The goal was to determine MMP-12 post-MI mechanisms. Male C57BL/6J mice (3–6 months old) were subjected to left coronary artery ligation. Saline or the RXP 470.1 MMP-12 inhibitor (MMP-12i; 0.5 mg/kg/day) were delivered by osmotic mini-pump beginning 3h post-MI, and mice were sacrificed at days (d)1, 3, 5 or 7 post-MI and compared to d0 controls (mice without MI; n=6–12/group/time). MMP-12 expression increased early post-MI, and contrary to expected, neutrophils were a surprising early cellular source for MMP-12. MMP-12i reduced MMP-12 activity 33±1% at d1 post-MI. Despite similar infarct areas and survival rates, MMP-12i led to greater LV dilation and worsened LV function. At d7 post-MI, MMP-12i prolonged pro-inflammatory cytokine upregulation (IL1r1, IL6ra, IL11, and Cxcr5) and decreased CD44 (both gene and protein levels). Hyaluronan (HA), a CD44 ligand, was elevated at d1 and d7 post-MI with MMP12i, as a result of decreased fragmentation. Because CD44-HA regulates neutrophil removal, apoptosis markers were evaluated. Caspase 3 increased, while cleaved caspase 3 levels decreased in MMP-12i group at d7 post-MI, indicating reduced neutrophil apoptosis. In isolated neutrophils, active MMP-12 directly stimulated CD44, caspase 3, and caspase 8 expression. Our results reveal a novel protective mechanism for MMP-12 in neutrophil biology. Post-MI, MMP-12i impaired CD44-HA interactions to suppress neutrophil apoptosis and prolong inflammation, which worsened LV function.
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影响因子：
3.7
作者：
Maugeri N;Rovere-Querini P;Evangelista V;Godino C;Demetrio M;Baldini M;Figini F;Coppi G;Slavich M;Camera M;Bartorelli A;Marenzi G;Campana L;Baldissera E;Sabbadini MG;Cianflone D;Tremoli E;D'Angelo A;Manfredi AA;Maseri A
通讯作者：
Maseri A
DOI：
10.1161/atvbaha.110.219147
发表时间：
2011-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnson JL;Devel L;Czarny B;George SJ;Jackson CL;Rogakos V;Beau F;Yiotakis A;Newby AC;Dive V
通讯作者：
Dive V
影响因子：
10
作者：
Churg, Andrew;Wang, Rona;Wright, Joanne L.
通讯作者：
Wright, Joanne L.
影响因子：
4.6
作者：
Paulsson, J. M.;Moshfegh, A.;Lundahl, J.
通讯作者：
Lundahl, J.
影响因子：
2.8
作者：
Ma, Yonggang;Chiao, Ying Ann;Zhang, Jianhua;Manicone, Anne M.;Jin, Yu-Fang;Lindsey, Merry L.
通讯作者：
Lindsey, Merry L.