Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice
Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice
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DOI：
10.1113/jphysiol.2010.202366
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发表时间：
2011-04-01
影响因子：
5.5
通讯作者：
Virag, Jitka A. I.
中科院分区：
文献类型：
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作者：
Dries, Jessica L.;Kent, Susan D.;Virag, Jitka A. I.
非技术概述心肌梗死后，心肌受到不可逆的损伤，随着时间的推移，这可能导致心力衰竭。目前正在研究减少缺血性损伤、增强新血管生长和/或替换受损心肌的策略。我们已经确定了一种新的非血管生成作用ephrinA 1，膜结合配体受体酪氨酸激酶，在促进非再灌注心肌梗死后心肌组织挽救。在损伤时用这种蛋白质治疗心脏可以减少梗死面积和整体损伤，可能是通过防止缺血后心肌细胞的损失。进一步的研究正在进行中，以确定发生这种情况的细胞机制和不良重塑的程度是attenuated.The目的是调查的作用，心肌内注射嵌合ephrinA 1-Fc在调制的损伤和炎症的程度在非再灌注心肌梗死（MI）。我们的研究结果表明，在B6129 s小鼠永久性冠状动脉结扎后立即向边缘区心肌内注射6 μ g ephrinA 1-Fc，导致MI后4天梗死面积减少50%，坏死减少64%，心室扩张减少35%，左心室游离壁变薄减少32%。在梗死区，Ly 6 G+中性粒细胞密度降低57%，CD 45+白细胞密度降低21%。在ephrinA 1-Fc处理的心脏中，心肌细胞损伤也减少，如血清心肌肌钙蛋白I降低54%所证明的。此外，我们观察到使用ephrinA 1-Fc给药后，切割的PARP减少，BAG-1蛋白表达增加，磷酸化AKT/总AKT蛋白增加，NF-κ B蛋白减少，表明细胞存活率提高。在已知在小鼠中表达的八种EphA受体（A1-A8）中，RT-PCR显示A1-A4、A6和A7在未损伤的成年心肌中表达。MI后EphA 1-A3和EphA 7的表达显着增加，而EphA 6的表达下降。用ephrinA 1-Fc处理进一步增加EphA 1和EphA 2基因表达，并导致EphA 4增加2倍。这些受体的上调和组合活化可促进组织存活。我们已经确定了一个新的，有益的作用ephrinA 1-Fc管理在MI的时间，并提出这是一个有前途的新的目标，在非再灌注心肌梗死挽救。更多的实验正在进行中，以确定受体表达细胞类型以及受体激活的功能影响。
Non-technical summaryFollowing a myocardial infarction, cardiac muscle becomes irreversibly damaged and over time this may lead to heart failure. Strategies to reduce ischaemic damage, enhance new vessel growth, and/or replace damaged heart muscle are currently being investigated. We have identified a novel non-angiogenic role for ephrinA1, a membrane-bound ligand receptor tyrosine kinase, in promoting myocardial tissue salvage after non reperfused myocardial infarction. Treating the heart with this protein at the time of injury reduced infarct size and overall damage, presumably by preventing cardiomyocyte loss after ischaemia. Further studies are in progress to determine the cellular mechanisms by which this occurs and the extent to which adverse remodelling is attenuated.The purpose of this study was to investigate the role of intramyocardial administration of chimeric ephrinA1-Fc in modulating the extent of injury and inflammation in non reperfused myocardial infarction (MI). Our results show that intramyocardial injection of 6 mu g ephrinA1-Fc into the border zone immediately after permanent coronary artery ligation in B6129s mice resulted in 50% reduction of infarct size, 64% less necrosis, 35% less chamber dilatation and 32% less left ventricular free wall thinning at 4 days post-MI. In the infarct zone, Ly6G+ neutrophil density was 57% reduced and CD45+ leukocyte density was 21% reduced. Myocyte damage was also reduced in ephrinA1-Fc-treated hearts, as evidenced by 54% reduced serum cardiac troponin I. Further, we observed decreased cleaved PARP, increased BAG-1 protein expression, increased phosphorylated AKT/total AKT protein, and reduced NF-kappa B protein with ephrinA1-Fc administration, indicating improved cellular survival. Of the eight EphA receptors known to be expressed in mice (A1-A8), RT-PCR revealed that A1-A4, A6 and A7 were expressed in the uninjured adult myocardium. Expression of EphA1-A3 and EphA7 were significantly increased following MI while EphA6 expression decreased. Treatment with ephrinA1-Fc further increased EphA1 and EphA2 gene expression and resulted in a 2-fold increase in EphA4. Upregulation and combinatorial activation of these receptors may promote tissue survival. We have identified a novel, beneficial role for ephrinA1-Fc administration at the time of MI, and propose this as a promising new target for infarct salvage in non reperfused MI. More experiments are in progress to identify receptor-expressing cell types as well as the functional implications of receptor activation.