Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy

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.

Long noncoding RNA TUG1 contributes to cerebral ischaemia/reperfusion injury by sponging mir‐145 to up‐regulate AQP4 expression

“…Together, these data support the concept that TUG1 is associated with cerebral IRI and functions as a positive regulator in IRI progression. A new mechanism has been proposed in which lncRNA H19 induces cerebral ischaemia‐reperfusion injury and more recently, Weixin et al demonstrated that lncRNA MALAT1 inhibits apoptosis induced by oxygen‐glucose deprivation and reoxygenation in human brain microvascular endothelial cells. From these studies, a broader understanding of the mechanisms of action of more lncRNAs may further the development of new therapeutic strategies for cerebral IRI.…”

Circular RNA Expression Profiles Alter Significantly in Mouse Brain After Transient Focal Ischemia

“…7 Furthermore, lncRNAs C2dat1 and NILR were shown to promote neuronal survival in the ischemic brain by modulating NF-κB signaling and inhibiting p53 signaling, respectively, 37,38 whereas lncRNAs H19 and TUG1 were shown to promote secondary ischemic brain damage by activating autophagy, apoptosis and p53, respectively. 39–41 A recent study further demonstrated that lncRNA MALAT1 induced after focal ischemia is neuroprotective by curtailing inflammation and apoptosis. 9 …”

Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1–Dependent M1 Microglial Polarization

“…7 However, the clinical value of H19 as a diagnostic and prognostic marker, as well as its relevance as a potential intervention target for ischemic stroke, requires further investigation.…”

“…3 Polymorphisms of the H19 gene have been demonstrated to alter its expression and are associated with risk factors for cardiovascular and cerebrovascular disease, such as obesity and high blood pressure. [4][5][6][7] H19 is strongly expressed during embryogenesis and subsequently downregulated after birth, but can be reactivated under hypoxic conditions. 8,9 Thus, we hypothesized that H19 might participate in the pathogenesis of ischemic stroke.…”