The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction
The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction
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双功能SDF-1-AnxA5融合蛋白可保护心肌梗塞后的心脏功能。
DOI：
10.1111/jcmm.14640
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发表时间：
2019-11-01
影响因子：
5.3
通讯作者：
Chen, Mao
中科院分区：
文献类型：
--
作者：
Huang, Fang-Yang;Xia, Tian-Li;Chen, Mao
基质细胞衍生因子-1（SDF-1）是一种保护心脏免受缺血性损伤的细胞因子。然而，天然SDF-1在促进心肌修复方面的有益作用受到其在缺血心肌中的低浓度的限制。Annexin V（AnxA 5）可以精确地检测体内死亡细胞。由于心肌梗死后大量心肌细胞死亡，我们假设AnxA 5可以作为一个锚携带SDF-1缺血心肌。在本研究中，我们构建了SDF-1和AnxA 5结构域的融合蛋白。受体竞争实验表明，SDF-1-AnxA 5与SDF-1受体CXCR 4具有较高的结合亲和力。SDF-1-AnxA 5可显著促进AKT和ERK的磷酸化，诱导细胞的趋化反应、血管生成和存活。结合膜实验和免疫荧光实验表明，AnxA 5结构域具有特异性识别缺氧损伤细胞并与缺氧损伤细胞结合的能力。此外，经外周静脉给予SDF-1-AnxA 5可在体内梗死心肌处积聚。用SDF-1-AnxA 5治疗小鼠心肌梗死后的细胞凋亡减弱，血管生成增强，梗死面积减小，心功能改善。我们的研究结果表明，双功能SDF-1-AnxA 5可以特异性结合死细胞。双功能SDF-1-AnxA 5的全身给药有效地提供了心肌梗死后的心脏保护。
Stromal cell-derived factor-1 (SDF-1) is a well-characterized cytokine that protects heart from ischaemic injury. However, the beneficial effects of native SDF-1, in terms of promoting myocardial repair, are limited by its low concentration in the ischaemic myocardium. Annexin V (AnxA5) can precisely detect dead cells in vivo. As massive cardiomyocytes die after MI, we hypothesize that AnxA5 can be used as an anchor to carry SDF-1 to the ischaemic myocardium. In this study, we constructed a fusion protein consisting of SDF-1 and AnxA5 domains. The receptor competition assay revealed that SDF-1-AnxA5 had high binding affinity to SDF-1 receptor CXCR4. The treatment of SDF-1-AnxA5 could significantly promote phosphorylation of AKT and ERK and induce chemotactic response, angiogenesis and cell survival in vitro. The binding membrane assay and immunofluorescence revealed that AnxA5 domain had the ability to specifically recognize and bind to cells injured by hypoxia. Furthermore, SDF-1-AnxA5 administered via peripheral vein could accumulate at the infarcted myocardium in vivo. The treatment with SDF-1-AnxA5 attenuated cell apoptosis, enhanced angiogenesis, reduced infarcted size and improved cardiac function after mouse myocardial infarction. Our results suggest that the bifunctional SDF-1-AnxA5 can specifically bind to dead cells. The systemic administration of bifunctional SDF-1-AnxA5 effectively provides cardioprotection after myocardial infarction.