Melatonin (MEL) has been demonstrated to exert a protective effect against subarachnoid hemorrhage (SAH), and nitric oxide (NO) has been shown to play an important role in the pathogenesis of vasospasm. This study aims to explore the underlying molecular mechanisms of MEL in the control of vasospasm following SAH. MEL administration attenuates SAH-induced vasospasm and neurobehavioral deficits. Expressions of H19, eNOS, and miR-675 are low in the SAH group, while expressions of miR-138 and HIF1α are high in the SAH group. Also, MEL treatment upon SAH rats completely restores the dysregulation of H19, eNOS, miR-675, miR-138, and HIF1α to their normal levels. Moreover, MEL dose dependently increases the luciferase activity of H19 promoter and hence the expression of H19. Additionally, H19 directly targets miR-675 and miR-138 to increase miR-675 expression and inhibit miR-138 expression. As virtual target genes of miR-675 and miR-138, respectively, HIF1α and eNOS are also regulated by the treatment with MEL. In particular, MEL treatment increases the expression of miR-675 and eNOS level while decreasing the expression of miR-138 and HIF1α in a dose dependent manner. Our study found that MEL ameliorates post-SAH vasospasm by regulating the expression of eNOS and HIF1α via the H19/miR-138/eNOS/NO and H19/miR-675/HIF1α signaling pathways.

中文翻译：

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MEL 通过 H19/miR-138/eNOS/NO 和 H19/miR-675/HIF1α 影响 eNOS 和 HIF1α 的表达来改善 SAH 后脑血管痉挛


褪黑激素（MEL）已被证明对蛛网膜下腔出血（SAH）具有保护作用，一氧化氮（NO）已被证明在血管痉挛的发病机制中发挥重要作用。本研究旨在探讨 MEL 控制 SAH 后血管痉挛的潜在分子机制。 MEL 给药可减轻 SAH 引起的血管痉挛和神经行为缺陷。 SAH 组中 H19、eNOS 和 miR-675 的表达较低，而 SAH 组中 miR-138 和 HIF1α 的表达较高。此外，MEL 治疗 SAH 大鼠可将 H19、eNOS、miR-675、miR-138 和 HIF1α 的失调完全恢复至正常水平。此外，MEL 剂量依赖性地增加 H19 启动子的荧光素酶活性，从而增加 H19 的表达。此外，H19直接靶向miR-675和miR-138以增加miR-675表达并抑制miR-138表达。分别作为 miR-675 和 miR-138 的虚拟靶基因，HIF1α 和 eNOS 也受到 MEL 治疗的调节。特别是，MEL 治疗以剂量依赖性方式增加 miR-675 的表达和 eNOS 水平，同时降低 miR-138 和 HIF1α 的表达。我们的研究发现，MEL 通过 H19/miR-138/eNOS/NO 和 H19/miR-675/HIF1α 信号通路调节 eNOS 和 HIF1α 的表达，从而改善 SAH 后血管痉挛。