Trim47 protects against hypoxic-ischaemic brain injury in neonatal rats by reducing brain microvascular endothelial inflammation and BBB disruption by interacting with ZO1.

Abstract

Hypoxic-ischaemic (HI) brain damage is the main contributor to neonatal brain damage and neurodevelopmental impairments. The E3 ubiquitin ligase tripartite motif 47 (Trim47) plays pivotal roles in regulating inflammation, autophagy, and apoptosis in the pathological processes of various diseases. However, the role of Trim47 in neonatal HI brain injury remains unknown. In vivo and in vitro models of neonatal rat brain HI and OGD/R-treated brain microvascular endothelial cells were established to investigate the roles of Trim47 and its underlying regulatory mechanism in neonatal brain injury. We found that Trim47 was highly expressed in brain microvascular endothelial cells, astrocytes and microglia and was downregulated in brain microvascular endothelial cells after neonatal HI injury in vivo and in vitro. Trim47 overexpression attenuated neonatal brain injury and blood-brain barrier (BBB) disruption following HI injury. It also improved long-term neurological outcomes and brain atrophy after HI injury. Trim47 overexpression increased the expression of the tight junction proteins ZO1 and occludin and suppressed MMP9 and AQP4 expression in brain microvascular endothelial cells after OGD/R. It also improved BBB function through ubiquitin conjugation to ZO1 and attenuated brain microvascular endothelial inflammation by suppressing NF-κB activation after OGD/R. However, Trim47 knockdown had the opposite effects. Thus, the present study demonstrates that the neuroprotective role of Trim47 in brain damage is achieved by preserving BBB function through interaction with ZO1 and by reducing brain microvascular endothelial inflammation through the suppression of NF-κB activation after neonatal HI injury.