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

Abstract

Objective Hypoxic–ischemic (HI)-related brain injury, especially HI encephalopathy (HIE) is a leading cause of morbidity and disability in newborns. Long noncoding RNAs (lncRNAs) are implicated in the progress of HI brain damage. However, the mechanisms underlying the regulatory effects of lncRNA H19 on autophagy in HIE remain unknown. This study was designed to identify the potential mechanisms involving lncRNA H19 in HIE. Study Design We selected three HIE newborns and three healthy newborns for neonatal behavioral neurological assessment and screened the differentially expressed lncRNAs by microarray analysis and detected H19 expression in serum. After that, neonatal HIE rats were established and injected with H19 overexpression lentivirus vector or autophagy activator Rapa. The structure and apoptotic levels of brain tissue were observed, and righting reflex and geotaxis reflex were utilized to evaluate the short-term neurological function of HIE rats. The Morris water maze was performed to measure the long-term neurological functions of HIE rats. The binding relationships among H19/miR-19b/protein kinase B3 (Akt3) were verified. Levels of Akt3- and autophagy-related proteins were measured. Results H19 was upregulated in HIE newborns and rat models. The areas of cerebral infarction and apoptosis in neonatal HIE rats were increased, and the nerve functions were compromised. The overexpression of H19 alleviated nerve damage of neonatal HIE rats, and reduced autophagy of brain tissue. H19 upregulated Akt3 as a miR-29b sponge. The protective effects of overexpression of H19 on brain tissue and nerve functions of neonatal HIE rats were partially reversed by autophagy activator. Conclusion H19 improved the brain tissue and alleviated nerve damage of neonatal HIE rats by upregulating the Akt3/mTOR pathway as a miR-29b sponge. Key Points

Circular RNA Sirtuin1 represses pulmonary artery smooth muscle cell proliferation, migration and autophagy to ameliorate pulmonary hypertension via targeting microRNA-145-5p/protein kinase-B3 axis

“…The alteration of multiple intracellular and extracellular signals is able to be sensed [ 32 ]. Additionally, the speed of autophagy is available to be activated or repressed [ 33 , 34 ]. In this study, augmentation of circSIRT1 on the advancement with autophagy of PAMSC was rescued via knocking down Akt3.…”

An update on the functional roles of long non‑coding RNAs in ischemic injury (Review)

“…In a study in 2020, the researchers established a neonatal rat model of hypoxic-ischemic encephalopathy (HIE), which exhibited an increased area of cerebral infarction, apoptosis and impaired neurological function in neonatal rats with HIE ( 40 ). That study confirmed that the overexpression of H19 functioned as a sponge for miR-29b and attenuated neural damage and reduced autophagy in brain tissue in neonatal rats with HIE by upregulating the Akt3/mTOR pathway.…”

“…That study confirmed that the overexpression of H19 functioned as a sponge for miR-29b and attenuated neural damage and reduced autophagy in brain tissue in neonatal rats with HIE by upregulating the Akt3/mTOR pathway. The effect produced by the overexpression of H19 could also be partially reversed by autophagy activators, which suggests that H19 affects autophagy ( 40 ). Furthermore, research on hypoxic-ischemic brain injury has confirmed that H19 overexpression is able to decrease miR-107 expression and increase VEGF expression, which results in the inhibition of neuronal apoptosis and the alleviation of cognitive dysfunction ( 41 ).…”

“…That study also revealed that H19 was involved in this process by regulating the miR-138-5p/p65 axis ( 39 ). Similarly, another study established in vitro and in vivo models of cerebral I/R ( 40 ). The results of that study confirmed that lncRNA H19 knockdown attenuated the OGD-mediated downregulation of miR-29b, SIRT1 and PGC-1α expression levels, which in turn ameliorated the OGD-induced increase in apoptosis and the concentration of inflammatory cytokines ( 40 ).…”

“…Similarly, another study established in vitro and in vivo models of cerebral I/R ( 40 ). The results of that study confirmed that lncRNA H19 knockdown attenuated the OGD-mediated downregulation of miR-29b, SIRT1 and PGC-1α expression levels, which in turn ameliorated the OGD-induced increase in apoptosis and the concentration of inflammatory cytokines ( 40 ). Another study also demonstrated that H19 functioned as a sponge for miR-1306-5p and triggered cerebral I/R-induced injury, and that the knockdown of H19 alleviated injury ( 41 ).…”