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

Abstract

Elevated expression of lncRNA <i>H19</i> (<i>H19</i>) 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 <i>H19</i> in ischemic brain stroke. This study found that <i>H19</i> 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 <i>H19</i> with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of <i>H19</i> 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 <i>H19</i> and the 3'-UTR of Id2 mRNA, resulting in the identification of the <i>H19</i>-miR-19a-Id2 axis. With biological studies, we also revealed that <i>H19</i>-miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified <i>H19</i>-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.