Abstract
Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke.
Highlights
Long non-coding RNA H19 was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury
The strength of association between H19 polymorphism and the risk of ischemic stroke was evaluated by odds ratio (OR) and 95% confidence interval (CI)
The present study demonstrated, for the first time, the upregulation of expression of Long non-coding RNAs (lncRNAs) H19 in the brain tissue of rat suffered from cerebral I/R injury
Summary
Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Recent studies revealed that lncRNAs participate in the regulation of protein expression through functioning as the molecular decoys, the mediators of signaling pathways, the molecular guides for transcriptional co-activators and the scaffold for the formation of functional complex [3]. Running title: LncRNA H19 in cerebral I/R injury cerebral ischemia and reperfusion (I/R) injury, which can stimulate the expression of lncRNA H19 through activating hypoxia induced factor 1α [10]. LncRNA H19 may take part in the regulation of autophagy, since studies demonstrated that lncRNA H19 has close relationship with apoptosis [7,10]
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