Ischemic injury in the heart is associated with low oxygen, leading to the damage of cardiomyocytes. The lncRNA-XIST is known to involve in post-ischemia myocardial remodeling. However, the roles and mechanism of XIST in the hypoxia-induced cardiomyocyte are still under investigation. Moreover, studies that elucidated the impaired glucose metabolism present new hallmark of ischemic cardiovascular injury. The objective of this study is to investigate the effects of lncRNA-XIST on cardiomyocyte injury under hypoxia. Here, we demonstrate that the XIST expressions of cardiomyocyte line, H9c2 were apparently suppressed by long-time hypoxia exposure under low glucose supply. On the contrary, miRNA-125b showed reverse expression pattern to XIST. We identified that XIST functioned as a ceRNA of miR-125b to downregulate its expression in both cell line and rat primary cardiomyocyte. Under low glucose supply, H9c2 cells exhibited increased susceptibility to hypoxia. We observed overexpression of XIST significantly elevated glycose metabolism rate under hypoxia, but overexpression of miR-125b inhibited glycose metabolism rate of cardiomyocyte under hypoxia. The glycolysis enzyme, hexokinase 2 (HK2) was validated as a direct target of miR-125b, which binds to the 3'-UTR region of HK2 mRNA in cardiomyocytes. Moreover, inhibition of miR-125b significantly protected the hypoxia-induced cardiomyocyte injury through restoration of glucose metabolism. Finally, we demonstrated that transfection of miR-125b in lncRNA-XIST overexpressed H9c2 cells effectively abolished the XIST-activated glucose metabolism and cardiomyocyte protection under hypoxia. The present study illustrates roles of the XIST-miR-125b-HK2 axis in the hypoxia-induced cardiomyocyte injury and proposes that maintaining glucose metabolism might be an effective approach for protection of cardiomyocyte injury.

中文翻译：

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lncRNA-XIST通过调节miR-125b-己糖激酶2轴来保护缺氧诱导的心肌细胞损伤。

心脏的缺血性损伤与低氧有关，导致心肌细胞的损伤。已知lncRNA-XIST参与缺血后心肌重塑。然而，XIST在缺氧诱导的心肌细胞中的作用和机制仍在研究中。此外，阐明葡萄糖代谢受损的研究提出了缺血性心血管损伤的新标志。这项研究的目的是调查lncRNA-XIST对缺氧条件下心肌细胞损伤的影响。在这里，我们证明了在低葡萄糖供应下长时间缺氧暴露可明显抑制心肌细胞系H9c2的XIST表达。相反，miRNA-125b表现出与XIST相反的表达模式。我们确定XIST充当miR-125b的ceRNA，以下调其在细胞系和大鼠原代心肌细胞中的表达。在低葡萄糖供应下，H9c2细胞对缺氧的敏感性增加。我们观察到XIST的过表达在缺氧条件下显着提高了糖代谢率，但miR-125b的过表达抑制了缺氧条件下心肌细胞的糖代谢率。糖酵解酶己糖激酶2（HK2）被确认为miR-125b的直接靶标，该miR-125b与心肌细胞HK2 mRNA的3'-UTR区结合。此外，通过恢复葡萄糖代谢，抑制miR-125b可以显着保护缺氧诱导的心肌细胞损伤。最后，我们证明，miR-125b在lncRNA-XIST过表达的H9c2细胞中的转染有效地消除了缺氧条件下XIST激活的葡萄糖代谢和对心肌细胞的保护。本研究说明了XIST-miR-125b-HK2轴在缺氧诱导的心肌细胞损伤中的作用，并提出维持葡萄糖代谢可能是保护心肌细胞损伤的有效方法。