Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Blvd, Greenville, NC 27834, USA.
J Physiol. 2011 Apr 1;589(Pt 7):1725-40. doi: 10.1113/jphysiol.2010.202366. Epub 2011 Jan 31.
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 μg 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-κB 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.
这项研究的目的是探究在非再灌注心肌梗死（MI）模型中，心肌内注射嵌合型 EphrinA1-Fc 对损伤和炎症程度的调节作用。我们的结果表明，在 B6129s 小鼠永久性冠状动脉结扎后立即向边界区心肌内注射 6μg EphrinA1-Fc，可使梗死面积减少 50%，梗死区坏死减少 64%，心室扩张减少 35%，左室游离壁变薄减少 32%，在 MI 后 4 天。在梗死区，Ly6G+中性粒细胞密度降低了 57%，CD45+白细胞密度降低了 21%。EphrinA1-Fc 治疗的心脏中肌细胞损伤也减少，血清心肌肌钙蛋白 I 降低了 54%。此外，我们观察到 EphrinA1-Fc 给药后，cleaved PARP 减少，BAG-1 蛋白表达增加，磷酸化 AKT/总 AKT 蛋白增加，NF-κB 蛋白减少，表明细胞存活得到改善。在已知在小鼠中表达的 8 种 EphA 受体（A1-A8）中，RT-PCR 显示 A1-A4、A6 和 A7 在未受损的成年心肌中表达。EphA1-A3 和 EphA7 的表达在 MI 后显著增加，而 EphA6 的表达减少。EphrinA1-Fc 治疗进一步增加了 EphA1 和 EphA2 基因的表达，并使 EphA4 的表达增加了 2 倍。这些受体的上调和组合激活可能促进组织存活。我们已经确定 EphrinA1-Fc 在 MI 时的一种新的、有益的作用，并提出这是一种有前途的非再灌注 MI 中梗死挽救的新靶点。更多的实验正在进行中，以确定表达受体的细胞类型以及受体激活的功能意义。
