EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction
EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction
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DOI：
10.1161/circulationaha.117.029980
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发表时间：
2017-11-07
期刊：
影响因子：
37.8
通讯作者：
Wollert, Kai C.
中科院分区：
文献类型：
--
作者：
Reboll, Marc R.;Korf-Klingebiel, Mortimer;Wollert, Kai C.
背景：急性心肌梗死（MI）后骨髓细胞治疗的临床试验大多产生中性结果。用特定的骨髓细胞来源的分泌蛋白治疗可能提供一种替代的生物学方法来改善MI后的组织修复和心脏功能。我们最近进行了一个生物信息学分泌组分析急性心肌梗死患者的骨髓细胞，发现了一个特点不佳的分泌蛋白，EMC10（内质网膜蛋白复合物亚基10），显示在血管生成screen.Methods的活动：我们研究了EMC10及其小鼠同源物（EMC10）在培养的内皮细胞和梗死心脏外植体的血管生成潜力。我们定义了心肌梗死后Emc10的细胞来源和功能，使用野生型，Emc10缺陷型和Emc10骨髓嵌合小鼠进行短暂的冠状动脉结扎。此外，我们探讨了心肌梗死后，在心力衰竭倾向FVB/N mice. Results：EMC10的渗透压微泵传递的治疗潜力通过小GTP酶，p21激活的激酶，和p38丝裂原激活蛋白激酶（MAPK）-MAPK激活的蛋白激酶2（MK2）途径，以促进肌动蛋白聚合和内皮细胞迁移。证实了这些信号传导事件在急性MI背景下的重要性，Emc 10通过p38 MAPK-MK 2刺激梗死小鼠心脏外植体的内皮细胞生长。在MI后野生型小鼠的左心室梗死区和循环中，emc10蛋白丰度增加。在急性心肌梗死患者的左心室组织样本中，Emc 10表达也增加。骨髓来源的单核细胞和巨噬细胞是梗塞小鼠心脏中Emc 10的主要来源。Emc 10 KO小鼠在基线时未显示心血管表型。然而，MI后，KO小鼠梗死边缘区的毛细血管化受损，与野生型小鼠相比，动物出现更大的梗死瘢痕和更明显的左心室重塑。移植野生型骨髓细胞的KO小鼠挽救了血管生成缺陷并改善了左心室重构。治疗FVB/N小鼠与重组Emc10增强梗死边缘区毛细血管化和左心室remodeling.Conclusions产生持续的有益影响：我们已经确定了Emc10作为一个以前未知的血管生成生长因子，是由骨髓来源的单核细胞和巨噬细胞作为内源性适应性反应的一部分，可以增强治疗，以修复心肌梗死后的心脏。
Background: Clinical trials of bone marrow cell-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific bone marrow cell-derived secreted proteins may provide an alternative biological approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in bone marrow cells from patients with acute MI and discovered a poorly characterized secreted protein, EMC10 (endoplasmic reticulum membrane protein complex subunit 10), showing activity in an angiogenic screen.Methods: We investigated the angiogenic potential of EMC10 and its mouse homolog (Emc10) in cultured endothelial cells and infarcted heart explants. We defined the cellular sources and function of Emc10 after MI using wild-type, Emc10-deficient, and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Furthermore, we explored the therapeutic potential of recombinant Emc10 delivered by osmotic minipumps after MI in heart failure-prone FVB/N mice.Results: Emc10 signaled through small GTPases, p21-activated kinase, and the p38 mitogen-activated protein kinase (MAPK)-MAPK-activated protein kinase 2 (MK2) pathway to promote actin polymerization and endothelial cell migration. Confirming the importance of these signaling events in the context of acute MI, Emc10 stimulated endothelial cell outgrowth from infarcted mouse heart explants via p38 MAPK-MK2. Emc10 protein abundance was increased in the infarcted region of the left ventricle and in the circulation of wild-type mice after MI. Emc10 expression was also increased in left ventricular tissue samples from patients with acute MI. Bone marrow-derived monocytes and macrophages were the predominant sources of Emc10 in the infarcted murine heart. Emc10 KO mice showed no cardiovascular phenotype at baseline. After MI, however, capillarization of the infarct border zone was impaired in KO mice, and the animals developed larger infarct scars and more pronounced left ventricular remodeling compared with wild-type mice. Transplanting KO mice with wild-type bone marrow cells rescued the angiogenic defect and ameliorated left ventricular remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border-zone capillarization and exerted a sustained beneficial effect on left ventricular remodeling.Conclusions: We have identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI.