Coronary Serum Exosomes Derived from Patients with Myocardial Ischemia Regulate Angiogenesis through the miR-939-mediated Nitric Oxide Signaling Pathway.
Coronary Serum Exosomes Derived from Patients with Myocardial Ischemia Regulate Angiogenesis through the miR-939-mediated Nitric Oxide Signaling Pathway.
复制标题
心肌缺血患者冠状动脉血清外泌体通过 miR-939 介导的一氧化氮信号通路调节血管生成
作者：
Li H;Liao Y;Gao L;Zhuang T;Huang Z;Zhu H;Ge J
原理：血管生成是缺血后组织修复和再生的关键步骤。循环外泌体在血管生成信号转导中的作用尚未得到很好的阐明。因此，本研究旨在研究心肌缺血患者冠状动脉血清外泌体对血管生成的影响，并阐明其潜在机制。方法和结果：根据纳入和排除标准纳入患者。从血管造影导管获得冠状动脉血。纯化血清外泌体，并通过其特异性形态和表面标记物进行表征。体外分析显示，与来自健康对照的外泌体（con-Exo）相比，来自心肌缺血患者的外泌体（isc-Exo）增强了内皮细胞增殖、迁移和管形成。在小鼠后肢缺血模型中，血液灌注和组织学染色表明，与con-Exo相比，isc-Exo显著促进血流恢复并增强新生血管形成。此外，我们发现心肌细胞，而不是心脏成纤维细胞或内皮细胞，在缺血应激下开始释放外泌体;心肌细胞可能是冠状动脉血清中生物活性外泌体的来源。此外，微阵列分析表明miR-939- 5 p在isc-Exo中显著下调。通过敲低和过表达分析，我们发现miR-939- 5 p通过靶向iNOS调节血管生成。miR-939- 5 p抑制iNOS的表达及其活性，减弱内皮NO的产生，并最终损害血管生成。结论：心肌缺血患者来源的Exosomes通过miR-939-iNOS-NO途径促进血管生成。我们的研究强调了冠状动脉血清外泌体在心肌缺血患者中作为重要的血管生成信使。
Rationale: Angiogenesis is a crucial step towards tissue repair and regeneration after ischemia. The role of circulating exosomes in angiogenic signal transduction has not been well elucidated. Thus, this study aims to investigate the effects of coronary serum exosomes from patients with myocardial ischemia on angiogenesis and to elucidate the underlying mechanisms. Methods and Results: The patients were enrolled according to the inclusion and exclusion criteria. Coronary blood was obtained from the angiography catheter. Serum exosomes were purified and characterized by their specific morphology and surface markers. In vitro analysis showed that compared to exosomes from healthy controls (con-Exo), exosomes from patients with myocardial ischemia (isc-Exo) enhanced endothelial cell proliferation, migration and tube formation. In a mouse hind-limb ischemia model, blood perfusion and histological staining demonstrated that isc-Exo significantly promoted blood flow recovery and enhanced neovascularization compared to con-Exo. Further, we revealed that cardiomyocytes, but not cardiac fibroblasts or endothelial cells, were initiated to release exosomes under ischemic stress; cardiomyocytes might be the source of bioactive exosomes in coronary serum. In addition, microarray analysis indicated that miR-939-5p was significantly down-regulated in isc-Exo. By knockdown and overexpression analyses, we found that miR-939-5p regulated angiogenesis by targeting iNOS. miR-939-5p inhibited both iNOS's expression and its activity, attenuated endothelial NO production, and eventually impaired angiogenesis. Conclusions: Exosomes derived from patients with myocardial ischemia promote angiogenesis via the miR-939-iNOS-NO pathway. Our study highlights that coronary serum exosomes serve as an important angiogenic messenger in patients suffering from myocardial ischemia.
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影响因子：
7.4
作者：
Mao, Mao;Sudhahar, Varadarajan;Ansenberger-Fricano, Kristine;Fernandes, Denise C.;Tanaka, Leonardo Y.;Fukai, Tohru;Laurindo, Francisco R. M.;Mason, Ronald P.;Vasquez-Vivar, Jeannette;Minshall, Richard D.;Stadler, Krisztian;Bonini, Marcelo G.
通讯作者：
Bonini, Marcelo G.
DOI：
10.1016/j.bbrc.2017.01.085
发表时间：
2017-02-26
影响因子：
3.1
作者：
Hou, Shiqiang;Fang, Ming;Li, Xinming
通讯作者：
Li, Xinming
影响因子：
16.6
作者：
Lai, Charles P.;Kim, Edward Y.;Badr, Christian E.;Weissleder, Ralph;Mempel, Thorsten R.;Tannous, Bakhos A.;Breakefield, Xandra O.
通讯作者：
Breakefield, Xandra O.
影响因子：
5.3
作者：
Vrijsen KR;Sluijter JP;Schuchardt MW;van Balkom BW;Noort WA;Chamuleau SA;Doevendans PA
通讯作者：
Doevendans PA
影响因子：
1.9
作者：
Gray WD;Mitchell AJ;Searles CD
通讯作者：
Searles CD