急性ST段抬高型心肌梗死患者动员的CD34+祖细胞促血管生成活性增加：微小RNA-378差异表达的作用

Increased Proangiogenic Activity of Mobilized CD34+ Progenitor Cells of Patients With Acute ST-Segment-Elevation Myocardial Infarction: Role of Differential MicroRNA-378 Expression.

作者信息

Templin Christian, Volkmann Julia, Emmert Maximilian Y, Mocharla Pavani, Müller Maja, Kraenkel Nicolle, Ghadri Jelena-R, Meyer Martin, Styp-Rekowska Beata, Briand Sylvie, Klingenberg Roland, Jaguszewski Milosz, Matter Christian M, Djonov Valentin, Mach Francois, Windecker Stephan, Hoerstrup Simon P, Thum Thomas, Lüscher Thomas F, Landmesser Ulf

机构信息

From the Department of Cardiology, University Heart Center (C.T., P.M., M.M., J.-R.G., M.J., C.M.M., T.F.L.), Department of Cardiovascular Surgery, Department of Surgical Research (M.Y.E., S.P.H.), University Hospital Zurich, Switzerland; Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Germany (J.V.); Department of Cardiology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Germany (N.K., U.L.); Institute of Anatomy, University of Berne, Switzerland (B.S.-R., V.D.); Division of Cardiology, Kantonsspital Frauenfeld, Switzerland (M.M.); Division of Cardiology, Kerckhoff Klinik, Bad Nauheim, Germany (R.K.); Center for Molecular Cardiology, Schlieren Campus and Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Switzerland (S.B., T.F.L.); First Department of Cardiology, Medical University of Gdansk, Poland (M.J.); Department of Cardiology, University of Geneva, Switzerland (F.M.); Department of Cardiology, University Hospital Bern, Switzerland (S.W.); Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany (T.T.); and National Heart and Lung Institute, Imperial College London, United Kingdom (T.T.).

出版信息

Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):341-349. doi: 10.1161/ATVBAHA.116.308695. Epub 2016 Dec 29.

DOI:10.1161/ATVBAHA.116.308695

PMID:28062497

Abstract

OBJECTIVE

Proangiogenic effects of mobilized bone marrow-derived stem/progenitor cells are essential for cardiac repair after myocardial infarction. MicroRNAs (miRNA/miR) are key regulators of angiogenesis. We investigated the differential regulation of angio-miRs, that is, miRNAs regulating neovascularization, in mobilized CD34 progenitor cells obtained from patients with an acute ST-segment-elevation myocardial infarction (STEMI) as compared with those with stable coronary artery disease or healthy subjects.

APPROACH AND RESULTS

CD34 progenitor cells were isolated from patients with STEMI (on day 0 and day 5), stable coronary artery disease, and healthy subjects (n=27). CD34 progenitor cells of patients with STEMI exhibited increased proangiogenic activity as compared with CD34 cells from the other groups. Using a polymerase chain reaction-based miRNA-array and real-time polymerase chain reaction validation, we identified a profound upregulation of 2 known angio-miRs, that are, miR-378 and let-7b, in CD34 cells of patients with STEMI. Especially, we demonstrate that miR-378 is a critical regulator of the proangiogenic capacity of CD34 progenitor cells and its stimulatory effects on endothelial cells in vitro and in vivo, whereas let-7b upregulation in CD34 cells failed to proof its effect on endothelial cells in vivo.

CONCLUSIONS

The present study demonstrates a significant upregulation of the angio-miRs miR-378 and let-7b in mobilized CD34 progenitor cells of patients with STEMI. The increased proangiogenic activity of these cells in patients with STEMI and the observation that in particular miR-378 regulates the angiogenic capacity of CD34 progenitor cells in vivo suggest that this unique miRNA expression pattern represents a novel endogenous repair mechanism activated in acute myocardial infarction.

摘要

目的

动员的骨髓源干细胞/祖细胞的促血管生成作用对心肌梗死后的心脏修复至关重要。微小RNA（miRNA/miR）是血管生成的关键调节因子。我们研究了急性ST段抬高型心肌梗死（STEMI）患者与稳定型冠状动脉疾病患者或健康受试者相比，在动员的CD34祖细胞中血管生成相关miRNA（即调节新生血管形成的miRNA）的差异调节情况。

方法与结果

从STEMI患者（第0天和第5天）、稳定型冠状动脉疾病患者和健康受试者中分离出CD34祖细胞（n = 27）。与其他组的CD34细胞相比，STEMI患者的CD34祖细胞表现出增强的促血管生成活性。使用基于聚合酶链反应的miRNA阵列和实时聚合酶链反应验证，我们在STEMI患者的CD34细胞中发现2种已知的血管生成相关miRNA即miR - 378和let - 7b显著上调。特别是，我们证明miR - 378是CD34祖细胞促血管生成能力的关键调节因子，其在体外和体内对内皮细胞具有刺激作用，而CD34细胞中let - 7b的上调未能证明其在体内对内皮细胞的作用。

结论

本研究表明STEMI患者动员的CD34祖细胞中血管生成相关miRNA miR - 378和let - 7b显著上调。STEMI患者这些细胞促血管生成活性增加，以及特别是miR - 378在体内调节CD34祖细胞血管生成能力的观察结果表明，这种独特的miRNA表达模式代表了急性心肌梗死中激活的一种新的内源性修复机制。