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EGR1 knockdown alleviates the cerebral injury in rats with intracerebral hemorrhage (ICH) via STAT3/NF-κB pathway by reducing RXRα acetylation level

Brain EGR1 (early growth response protein 1) overexpression aggravates focal ischemic brain injury, but its role in intracerebral hemorrhage (ICH) induced cerebral injury remains obscure. In this study, a rat ICH model was established by injecting type VII collagenase into the brain, and EGR1 knockdown reversed the increase of hematoma area, neurological function score, brain water content, blood-brain barrier (BBB) permeability, inflammation, p300 and RXRα protein levels, as well as RXRα acetylation level induced by ICH. EGR1 expression was up-regulated in primary brain microvascular endothelial cells (BMECs), neurons, and astrocytes after ICH induction, and the up-regulation was most significant in BMECs. We also found that EGR1 promoted RXRα acetylation level by regulating p300 in BMECs. Subsequently, the BMECs were treated with OGD (oxygen glucose deprivation) plus hemin to simulate ICH condition. And silencing EGR1 rescued the upregulation of cell inflammation and the reduction of cell viability and TEER (transendothelial electric resistance) caused by OGD plus hemin via p300-mediated RXRα acetylation. Furthermore, the STAT3/NF-κB pathway was activated after treatment with OGD plus hemin, which was suppressed by silencing EGR1. And treatment with Stattic (an inhibitor of STAT3) restrained the effect of OGD plus hemin on NF-κB pathway activity, inflammation, cell viability and TEER. In conclusion, EGR1 increased RXRα acetylation level by regulating p300, thereby aggravating brain damage in ICH rat model and dysfunction in BMECs, which might through the STAT3/NF-κB pathway.

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S7024 Stattic Stattic, the first nonpeptidic small molecule, potently inhibits STAT3 activation and nuclear translocation with IC50 of 5.1 μM in cell-free assays, highly selectivity over STAT1. Stattic induces apoptosis. (169) (4)

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