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: · H19 overexpression reduces the nerve damage in neonatal HIE rats.. · H19 reduces autophagy in neonatal HIE rats by the miR-29b/Akt3/mTOR axis.. · Autophagy activator reverses the protection of H19 in neonatal HIE..