Affiliation:
1. Tianjin University of Traditional Chinese Medicine
2. Ganzhou people’s hospital
Abstract
Abstract
Background: Endothelial pyroptosis promotes cerebral ischemic-reperfusion injury (CIRI). Sodium Danshensu (SDSS) has been shown to attenuate CIRI and have anti-inflammatory properties in endothelial cells. Nevertheless, the mechanism of SDSS on endothelial pyroptosis after CIRI remains unclear. Objective: We aimed to investigate the efficacy and mechanism of SDSS for reducing endothelial pyroptosis. Methods: In vitro, the effect of SDSS alleviating CIRI was first confirmed by detecting pyroptosis and NLRP3 inflammasome related indicators in oxygen-glucose deprivation/reoxygen (OGD/R) treated bEnd3 cells. Further, CLIC4 was identified as a potential target of SDSS through protein microarray, molecular docking, and cellular thermal shift assay (CETSA). Following this, the translocation and expression of CLIC4, and chloride outflow were detected. Finally, CLIC4 was further tested, either overexpressed or knocked down, to determine whether it is a target of SDSS to inhibit endothelial pyroptosis. In vivo, neurological deficit scores and infarct volume were served to evaluate the effect of SDSS in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Further investigation of pyroptosis was conducted using the CLIC4/NLRP3/GSDMD pathway. Results: SDSS administration inhibited NLRP3 inflammasome mediated pyroptosis in vitro and vivo. As demonstrated by protein microarray, molecular docking and CETSA, SDSS bound strongly to CLIC4 and decreased its protein level, and inhibited its translocation from cytoplasm to cell membrane. Further, SDSS effectiveness was weakened by CLIC4 overexpression but not knockdown. Conclusion: The present study indicated that a beneficial effect of SDSS against CIRI was ascribed to block endothelial pyroptosis via binding to CLIC4, and then inhibiting chloride efflux-dependent NLRP3 inflammasome activation.
Publisher
Research Square Platform LLC
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