EMC10（内质网膜蛋白复合物亚基 10）是一种骨髓源性血管生成生长因子，可促进心肌梗死后的组织修复。

EMC10 (Endoplasmic Reticulum Membrane Protein Complex Subunit 10) Is a Bone Marrow-Derived Angiogenic Growth Factor Promoting Tissue Repair After Myocardial Infarction.

机构信息

From Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology (M.R.R., M.K.-K., S.K., E.B., I.R., Y.W., K.C.W.), Core Unit Proteomics, Institute of Toxicology (F.P., A.P.), Department of Biophysical Chemistry (J.F.), Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation, and Vascular Surgery (G.K., I.G.), Institute of Legal Medicine (M.K.), Institute of Physiological Chemistry (M.G.), and Department of Cardiology and Angiology (J.B.), Hannover Medical School, Germany; F. Hoffmann-La Roche, Pharma Research and Early Development, Basel, Switzerland (H.-J.S., M.B.); Department of Pathology and Department of Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Physiology and Cellular Biophysics and Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY (J.A.G.).

出版信息

Circulation. 2017 Nov 7;136(19):1809-1823. doi: 10.1161/CIRCULATIONAHA.117.029980. Epub 2017 Sep 20.

DOI:10.1161/CIRCULATIONAHA.117.029980

PMID:28931551

Abstract

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, -deficient, and 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. 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.

摘要

背景

急性心肌梗死（MI）后骨髓细胞为基础的治疗临床试验产生的结果大多为中性。治疗特定的骨髓细胞衍生的分泌蛋白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。我们最近在急性 MI 患者的骨髓细胞中进行了生物信息学分泌组分析，发现了一种特征不明显的分泌蛋白，EMC10（内质网膜蛋白复合物亚基 10），在血管生成筛选中具有活性。

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死心脏外植体中的血管生成潜力。我们使用野生型、-缺陷型和骨髓嵌合小鼠，在短暂性冠状动脉结扎后，定义了 MI 后 Emc10 的细胞来源和功能。此外，我们在易发生心力衰竭的 FVB/N 小鼠中，通过渗透型微泵递送重组 Emc10 后，探讨了其在 MI 中的治疗潜力。

结果

Emc10 通过小 GTPases、p21 激活激酶和 p38 丝裂原活化蛋白激酶（MAPK）-MAPK 激活的蛋白激酶 2（MK2）途径发出信号，促进肌动蛋白聚合和内皮细胞迁移。在急性 MI 的背景下证实这些信号事件的重要性，Emc10 通过 p38 MAPK-MK2 刺激梗死小鼠心脏外植体中的内皮细胞生长。Emc10 蛋白丰度在左心室梗死区和 MI 后野生型小鼠的循环中增加。Emc10 的表达在急性 MI 患者的左心室组织样本中也增加。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。KO 小鼠在基线时没有心血管表型。然而，在 MI 后，KO 小鼠的梗死边缘区的毛细血管化受损，与野生型小鼠相比，动物的梗死疤痕更大，左心室重构更明显。用野生型骨髓细胞移植 KO 小鼠可挽救血管生成缺陷，并改善左心室重构。用重组 Emc10 治疗 FVB/N 小鼠可增强梗死边缘区的毛细血管化，并对左心室重构产生持续的有益影响。