| First Author | Xue J | Year | 2019 |
| Journal | J Am Heart Assoc | Volume | 8 |
| Issue | 22 | Pages | e012885 |
| PubMed ID | 31718447 | Mgi Jnum | J:299382 |
| Mgi Id | MGI:6490705 | Doi | 10.1161/JAHA.119.012885 |
| Citation | Xue J, et al. (2019) Sphingomyelin Synthase 2 Inhibition Ameliorates Cerebral Ischemic Reperfusion Injury Through Reducing the Recruitment of Toll-Like Receptor 4 to Lipid Rafts. J Am Heart Assoc 8(22):e012885 |
| abstractText | Background Inflammation is recognized as an important contributor of ischemia/reperfusion (I/R) damage after ischemic stroke. Sphingomyelin synthase 2 (SMS2), the key enzyme for the biosynthesis of sphingomyelin, can function as a critical mediator of inflammation. In the present study, we investigated the role of SMS2 in a mouse model of cerebral I/R. Methods and Results Cerebral I/R was induced by 60-minute transient middle cerebral artery occlusion in SMS2 knockout (SMS2(-/-)) mice and wild-type mice. Brain injury was determined by neurological deficits and infarct volume at 24 and 72 hours after transient middle cerebral artery occlusion. Microglia activation and inflammatory factors were detected by immunofluorescence staining, flow cytometry, western blot, and RT-PCR. SMS2 deficiency significantly improved neurological function and minimized infarct volume at 72 hours after transient middle cerebral artery occlusion. The neuroprotective effects of SMS2 deficiency were associated with (1) suppression of microglia activation through Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells pathway and (2) downregulation of the level of galactin-3 and other proinflammatory cytokines. The mechanisms underlying the beneficial effects of SMS2 deficiency may include altering sphingomyelin components in lipid raft fractions, thus impairing the recruitment of Toll-like receptor 4 to lipid rafts and subsequently reducing Toll-like receptor 4/myeloid differentiation factor 2 complex formation on the surface of microglia. Conclusions SMS2 deficiency ameliorated inflammatory injury after cerebral I/R in mice, and SMS2 may be a key modulator of Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells activation by disturbing the membrane component homeostasis during cerebral I/R. |
