外泌体长链非编码 RNA TUG1 对心肌梗死的抗血管生成作用及远隔缺血预处理的调节作用。
Anti-angiogenic effect of exo-LncRNA TUG1 in myocardial infarction and modulation by remote ischemic conditioning.
机构信息
Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Division of Gastroenterological Rehabilitation, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
出版信息
Basic Res Cardiol. 2023 Jan 12;118(1):1. doi: 10.1007/s00395-022-00975-y.
The successful use of exosomes in therapy after myocardial infarction depends on an improved understanding of their role in cardiac signaling and regulation. Here, we report that exosomes circulating after myocardial infarction (MI) carry LncRNA TUG1 which downregulates angiogenesis by disablement of the HIF-1α/VEGF-α axis and that this effect can be counterbalanced by remote ischemic conditioning (RIC). Rats with MI induced through left coronary artery ligation without (MI model) and with reperfusion (ischemia/reperfusion I/R model) were randomized to RIC, or MI (I/R) or sham-operated (SO) control. Data from one cohort study and one randomized-controlled trial of humans with MI were also utilized, the former involving patients who had not received percutaneous coronary intervention (PCI) and the latter patients with PCI. Exosome concentrations did not differ between intervention groups (RIC vs. control) in rats (MI and I/R model) as well as humans (with and without PCI). However, MI and I/R exosomes attenuated HIF-1α, VEGF-α, and endothelial function. LncRNA TUG1 was increased in MI and I/R exosomes, but decreased in SO and RIC exosomes. HIF-1α expression was downregulated with MI and I/R exosomes but increased with RIC exosomes. Exosome inhibition suppressed HIF-1α upregulation through RIC exosomes. VEGF-α was identified as HIF-1α-regulated target gene. Knockdown of HIF-1α decreased VEGF-α, endothelial cell capability, and tube formation. Overexpression of HIF-1α exerted opposite effects. Transfection and co-transfection of 293 T cells with exosome-inhibitor GW4869 and HIF-1α inhibitor si-HIF-1α confirmed the exosomal-LncRNA TUG1/HIF-1α/VEGF-α pathway. LncRNA TUG1 is a potential therapeutic target after MI with or without reperfusion through PCI.
外泌体在心肌梗死后治疗中的成功应用取决于对其在心脏信号转导和调节中作用的深入理解。在这里，我们报告说，心肌梗死后循环中的外泌体携带 LncRNA TUG1，通过使 HIF-1α/VEGF-α 轴失活来抑制血管生成，而这种效应可以通过远程缺血预处理（RIC）来抵消。通过结扎左冠状动脉而不进行再灌注（缺血/再灌注 I/R 模型）诱导大鼠心肌梗死（MI 模型），并随机分为 RIC 组、MI（I/R）组或假手术（SO）对照组。还利用了一项队列研究和一项人类 MI 的随机对照试验的数据，前者涉及未接受经皮冠状动脉介入治疗（PCI）的患者，后者涉及接受 PCI 的患者。在大鼠（MI 和 I/R 模型）和人类（有和无 PCI）中，干预组（RIC 与对照组）之间的外泌体浓度没有差异。然而，MI 和 I/R 外泌体减弱了 HIF-1α、VEGF-α 和内皮功能。LncRNA TUG1 在 MI 和 I/R 外泌体中增加，但在 SO 和 RIC 外泌体中减少。HIF-1α 表达随 MI 和 I/R 外泌体下调，但随 RIC 外泌体上调。外泌体抑制通过 RIC 外泌体抑制 HIF-1α 的上调。VEGF-α 被鉴定为 HIF-1α 调节的靶基因。敲低 HIF-1α 降低了 VEGF-α、内皮细胞功能和管形成。过表达 HIF-1α 则产生相反的效果。用外泌体抑制剂 GW4869 和 HIF-1α 抑制剂 si-HIF-1α 转染和共转染 293T 细胞证实了外泌体-LncRNA TUG1/HIF-1α/VEGF-α 通路。LncRNA TUG1 是一种有或无再灌注经皮冠状动脉介入治疗后 MI 的潜在治疗靶点。
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