TEAD1 KNOCKDOWN IMPEDES THE INFLAMMATION AND FERROPTOSIS BY MEDIATING MMP3 IN CEREBRAL ISCHEMIA REPERFUSION

ABSTRACT: Background: Cerebral ischemia-reperfusion (IR) injury is a frequent complication of ischemic stroke with the adverse impact on the clinical prognosis. This study focused on the molecular mechanism associated with TEA domain transcription factor 1 (TEAD1) and matrix metalloproteinase 3 (MMP3) in cerebral IR. Methods:In vitro , IR model was established using oxygen-glucose deprivation/reoxygenation (OGD/R) in human brain microvascular endothelial cells (HBMVECs). TEAD1 and MMP3 mRNA and protein examination were performed by RT-qPCR and western blot. Cell viability and apoptosis were measured using cell counting kit-8 assay and flow cytometry. Enzyme-linked immunosorbent assay was conducted for detection of inflammatory cytokines. Ferroptosis was evaluated via kits. TEAD1 and MMP3 interaction was proved by RNA immunoprecipitation assay. In vivo , IR was induced in rats by middle cerebral artery occlusion-reperfusion (MCAO/R) model. Brain injury in rats was assessed by tetrazolium chloride staining, Evans blue extravasation, neurological function score, and cerebral water content detection. Results: OGD/R-induced the prominent upregulation of MMP3 in HBMVECs. After knockdown of MMP3, apoptosis, inflammation and ferroptosis were all mitigated in OGD/R-treated HBMVECs. TEAD1 could enhance MMP3 expression by targeting the promoter. TEAD1 silence impeded OGD/R-mediated inflammation and ferroptosis via reducing MMP3. In MCAO/R model, TEAD1 inhibition protected brain tissues of rats against cerebral IR injury by affecting MMP3. Conclusion: The above evidence elucidated that TEAD1 facilitated cerebra inflammation and ferroptosis in vitro and in vivo IR models through targeting MMP3, suggesting the involvement of TEAD1/MMP3 axis in cerebral IR injury.