TEAD1 knockdown impedes the inflammation and ferroptosis by mediating MMP3 in cerebral ischemia reperfusion.

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.