Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19
Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19
复制标题
阿托伐他汀通过上调长链非编码 RNA H19 增强间充质干细胞来源的外泌体对急性心肌梗死的治疗效果。
DOI：
10.1093/cvr/cvz139
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发表时间：
2020-02-01
影响因子：
10.8
通讯作者：
Yang, Yuejin
中科院分区：
文献类型：
--
作者：
Huang, Peisen;Wang, Li;Yang, Yuejin
目的：自然分泌的纳米囊泡，被称为外泌体，在干细胞介导的心脏保护中发挥重要作用。我们之前已经证明，阿托伐他汀（ATV）预处理可以改善大鼠急性心肌梗死（AMI）模型中间充质干细胞（MSCs）的心脏保护作用。本研究的目的是研究atv预处理的MSCs衍生的外泌体是否在AMI大鼠模型中表现出更强的心脏保护功能，如果是，则探讨其潜在机制。方法和结果：从对照MSCs （MSC-Exo）和atv预处理的MSCs （MSCATV-Exo）中分离外泌体，然后在体外缺氧和血清剥夺（H/SD）条件下或在急性梗死的Sprague-Dawley大鼠心脏中递送内皮细胞和心肌细胞。利用基因组学方法和功能研究探索ATV预处理激活的调控基因和通路。在体外，MSCATV-Exo加速了内皮细胞的迁移、管状结构的形成，并增加了内皮细胞的存活率，但没有增加心肌细胞的存活率，而MSCATV-Exo处理的内皮细胞衍生的外泌体阻止了H/ sd诱导的心肌细胞凋亡。在大鼠AMI模型中，与MSC-Exo相比，MSCATV-Exo可改善心功能恢复，进一步缩小梗死面积，减少心肌细胞凋亡。此外，MSCATV-Exo促进血管生成，抑制梗死周围区域IL-6和tnf - α的升高。在机制上，我们发现lncRNA H19是MSCATV-Exo调节miR-675表达、促血管生成因子VEGF和细胞间粘附分子-1激活的中介。与此一致的是，当atv预处理的MSCs中lncRNA H19被耗尽并通过lncRNA H19过表达来模拟时，MSCATV-Exo的心脏保护作用被取消。结论：atv预处理MSCs获得的外泌体可能通过促进内皮细胞功能而显著提高治疗AMI的疗效。LncRNA H19至少部分介导MSCATV-Exo在促进血管生成中的心脏保护作用。
Aims: Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms.Methods and results: Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-alpha in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19.Conclusion: Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.