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腺苷能刺激人内皮祖细胞的迁移。CXCR4 和 microRNA-150 的作用。

Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150.

机构信息

Laboratory of Cardiovascular Research, Public Research Centre-Health (CRP-Santé), Luxembourg, Luxembourg.

出版信息

PLoS One. 2013;8(1):e54135. doi: 10.1371/journal.pone.0054135. Epub 2013 Jan 9.

DOI:10.1371/journal.pone.0054135
PMID:23326587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3541240/
Abstract

BACKGROUND

Administration of endothelial progenitor cells (EPC) represents a promising option to regenerate the heart after myocardial infarction, but is limited because of low recruitment and engraftment in the myocardium. Mobilization and migration of EPC are mainly controlled by stromal cell-derived factor 1α (SDF-1α) and its receptor CXCR4. We hypothesized that adenosine, a cardioprotective molecule, may improve the recruitment of EPC to the heart.

METHODS

EPC were obtained from peripheral blood mononuclear cells of healthy volunteers. Expression of chemokines and their receptors was evaluated using microarrays, quantitative PCR, and flow cytometry. A Boyden chamber assay was used to assess chemotaxis. Recruitment of EPC to the infarcted heart was evaluated in rats after permanent occlusion of the left anterior descending coronary artery.

RESULTS

Microarray analysis revealed that adenosine modulates the expression of several members of the chemokine family in EPC. Among these, CXCR4 was up-regulated by adenosine, and this result was confirmed by quantitative PCR (3-fold increase, P<0.001). CXCR4 expression at the cell surface was also increased. This effect involved the A(2B) receptor. Pretreatment of EPC with adenosine amplified their migration towards recombinant SDF-1α or conditioned medium from cardiac fibroblasts. Both effects were abolished by CXCR4 blocking antibodies. Adenosine also increased CXCR4 under ischemic conditions, and decreased miR-150 expression. Binding of miR-150 to the 3' untranslated region of CXCR4 was verified by luciferase assay. Addition of pre-miR-150 blunted the effect of adenosine on CXCR4. Administration of adenosine to rats after induction of myocardial infarction stimulated EPC recruitment to the heart and enhanced angiogenesis.

CONCLUSION

Adenosine increases the migration of EPC. The mechanism involves A(2B) receptor activation, decreased expression of miR-150 and increased expression of CXCR4. These results suggest that adenosine may be used to enhance the capacity of EPC to revascularize the ischemic heart.

摘要

背景

内皮祖细胞(EPC)的给药代表了一种有前途的心肌梗死后心脏再生的选择,但由于其在心肌中的募集和植入有限。EPC 的动员和迁移主要由基质细胞衍生因子 1α(SDF-1α)及其受体 CXCR4 控制。我们假设,作为一种心脏保护分子的腺苷可能改善 EPC 向心脏的募集。

方法

从健康志愿者的外周血单核细胞中获得 EPC。使用微阵列、定量 PCR 和流式细胞术评估趋化因子及其受体的表达。使用 Boyden 室测定法评估趋化性。在大鼠左前降支冠状动脉永久性闭塞后,评估 EPC 向梗死心脏的募集。

结果

微阵列分析显示,腺苷调节 EPC 中趋化因子家族的几个成员的表达。其中,腺苷上调 CXCR4,这一结果通过定量 PCR 得到证实(增加 3 倍,P<0.001)。CXCR4 细胞表面表达也增加。这种作用涉及 A(2B)受体。EPC 用腺苷预处理可增强其向重组 SDF-1α或心脏成纤维细胞条件培养基的迁移。这两种作用均被 CXCR4 阻断抗体所阻断。腺苷在缺血条件下也增加了 CXCR4,同时降低了 miR-150 的表达。通过荧光素酶测定证实了 miR-150 与 CXCR4 的 3'非翻译区结合。添加前 miR-150 削弱了腺苷对 CXCR4 的作用。在诱导心肌梗死后向大鼠给予腺苷可刺激 EPC 向心脏募集并增强血管生成。

结论

腺苷增加 EPC 的迁移。其机制涉及 A(2B)受体激活、miR-150 表达降低和 CXCR4 表达增加。这些结果表明,腺苷可用于增强 EPC 使缺血心脏再血管化的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d253/3541240/e052dc01d623/pone.0054135.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d253/3541240/7f9a3d304fbb/pone.0054135.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d253/3541240/e052dc01d623/pone.0054135.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d253/3541240/595aab5fb815/pone.0054135.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d253/3541240/e052dc01d623/pone.0054135.g007.jpg

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