Background—Clinical trials of bone marrow cell (BMC)-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific BMC-derived secreted proteins may provide an alternative biologic approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in BMCs from patients with acute MI and discovered a poorly characterized secreted protein, endoplasmic reticulum membrane protein complex subunit 10 (EMC10), 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 (WT), Emc10-deficient (knockout, KO), and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Further, 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 WT mice after MI. Emc10 expression was also increased in left ventricular (LV) 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 LV remodeling compared to WT mice. Transplanting KO mice with WT BMCs rescued the angiogenic defect and ameliorated LV remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border zone capillarization and exerted a sustained beneficial effect on LV 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.

背景-急性心肌梗塞（MI）后基于骨髓细胞（BMC）的疗法的临床试验已产生了大部分中性的结果。用特定BMC衍生的分泌蛋白进行治疗可能会提供另一种生物方法，以改善MI后的组织修复和心脏功能。我们最近在急性心肌梗死患者的BMC中进行了生物信息学的分泌组分析，发现了分泌蛋白，内质网膜蛋白复合物亚基10（EMC10）表征不佳，在血管生成筛查中表现出活性。方法—我们研究了EMC10及其小鼠同源物（Emc10）在培养的内皮细胞和梗塞的心脏外植体中的血管生成潜力。我们使用野生型（WT）定义了MI后Emc10的细胞来源和功能，缺乏Emc10的小鼠（基因敲除，KO）和Emc10的骨髓嵌合小鼠进行了短暂的冠状动脉结扎。此外，我们探索了心衰多发的FVB / N小鼠中MI后由渗透微泵输送的重组Emc10的治疗潜力。结果-Emc10通过小的GTPases，p21激活的激酶和p38丝裂原激活的蛋白激酶（MAPK）-MAPK激活的蛋白激酶2（MK2）途径发出信号，从而促进肌动蛋白聚合和内皮细胞迁移。为了证实这些信号事件在急性心肌梗死中的重要性，Emc10通过p38 MAPK-MK2刺激了梗塞小鼠心脏外植体的内皮细胞生长。MI后，左心室梗塞区域和WT小鼠的循环中Emc10蛋白的丰度增加。在患有急性心肌梗死的患者的左心室（LV）组织样本中，Emc10表达也有所增加。骨髓来源的单核细胞和巨噬细胞是梗死小鼠心脏中Emc10的主要来源。Emc10KO小鼠在基线时未显示心血管表型。但是，MI后，KO小鼠的梗死边界区的毛细血管化受到损害，并且与WT小鼠相比，这些动物出现了更大的梗死疤痕和更明显的LV重塑。用野生型BMC移植KO小鼠可挽救血管新生缺陷并改善LV重塑。用重组Emc10处理FVB / N小鼠可增强梗死边界区的毛细血管化作用，并对LV重塑起持续的有益作用。结论—我们已经将Emc10鉴定为由骨髓衍生的单核细胞和巨噬细胞产生的先前未知的血管生成生长因子，它是内源性适应性反应的一部分，可以通过治疗增强其以修复心肌梗死后的心脏。