Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury

Abstract

Elevated expression of lncRNA H19 ( H19 ) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3’-UTR of Id2 mRNA, resulting in the identification of the H19 -miR-19a-Id2 axis. With biological studies, we also revealed that H19 -miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19 -miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.

Long Non-Coding RNA H19 Expression and Functional Polymorphism rs217727 Are Linked to Increased Ischemic Stroke Risk

“…In addition, we observed a signi cant increase in the lncRNA H19 expression levels of IS patients when compared to healthy controls. This result is consistent with previous studies that reported the upregulation of H19 in the peripheral blood of IS patients [25,33,34]. We evaluated H19 expression at three different times (0-24 hours [n = 39], 24-48 hours [n = 38], and 48-72 hours [n = 37] after stroke).…”

“…The results obtained from in vitro and in vivo experiments showed that H19 was upregulated following ischemic reperfusion injuries in the ischemic penumbra of animals, as well as in the neuroblastoma cell after oxygen-glucose deprivation and reperfusion (OGD/R)-induced injury [33,35,36]. We have little information about the basic mechanism of lncRNA H19 in IS.…”

“…Recently, Xiao et al reported neuronal apoptosis (both in vitro and in vivo) was reduced by the inhibition of H19 with siRNA. Also, the inhibition of H19 in ischemic rats signi cantly decreased brain infarct size, neurological de cit, and neuronal apoptosis [33]. Wang et al demonstrated that lncRNA H19 caused by activation of autophagy induces cerebral ischemia reperfusion damage [35].…”

Dexmedetomidine Postconditioning Alleviates Hypoxia/Reoxygenation Injury in Senescent Myocardial Cells by Regulating lncRNA H19 and m6A Modification

“…In particular, lncRNA can act as competitive endogenous RNA (ceRNA) to regulate microRNA expression [10]. lncRNA H19, a 2.3 kb noncoding RNA, reportedly has contradictory functions in cancer and, interestingly, ischemic disease [11][12][13][14]. H19 expression was upregulated by cerebral I/R as well as cellular oxygen-glucose deprivation/reperfusion, while H19 upregulation increased hypoxia-induced injury in H9c2 cells (i.e., rat myoblasts) [15,16].…”

Mechanisms Underlying Abnormal Expression of lncRNA H19 in Neonatal Hypoxic–Ischemic Encephalopathy

“…More recently, a new regulatory mechanism of miR sponge was proposed whereby H19 functions as a ceRNA, thereby modulating the depression of miR targets in hypoxia-induced neuronal apoptosis. 23 Similarly, H19 could target miR-29b-3p and protect hypoxia postconditioning against hypoxia-reoxygenation injury to senescent cardiomyocytes. 27 Activation of the Akt/mTOR axis negatively regulates apoptosis and autophagy, which is involved in the protection of miR-223 mimic against hypoxia-induced injury in H9c2 cells or neonatal rat cardiomyocytes.…”