RESUMEN
This study aimed to explore the biological role and molecular mechanism of long noncoding RNA (lncRNA) rhabdomyosarcoma 2-associated transcript (RMST) in regulating microglial activation. Mouse microglial BV2 cells were cultured to establish the cell model of cerebral ischemic stroke by oxygen-glucose deprivation (OGD). We observed highly expressed RMST, increased expression of M1, and decreased expression of M2 markers in BV2 microglial cells stimulated with OGD. These alterations were reversed by RMST knockdown. Activation of transforming growth factor-beta-activated kinase 1 (TAK1)-mediated nuclear factor-κB (NF-κB) pathway was observed upon OGD stimulation, which was promoted by RMST through competitively binding with heterogeneous nuclear ribonucleoprotein K (hnRNPK), confirmed by RNA pull down and RNA immunoprecipitation (RIP) assays. Furthermore, RMST overexpressing-BV2 cells effectively enhanced neuronal apoptosis. In conclusion, RMST promoted OGD-induced microglial M1 polarization by competitively interacting with hnRNPK via TAK1-mediated NF-κB pathway, which will provide a basis for understanding the pathogenesis of cerebrovascular diseases.
Asunto(s)
Glucosa/deficiencia , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Microglía/patología , FN-kappa B/metabolismo , Oxígeno/metabolismo , ARN Largo no Codificante/genética , Animales , Apoptosis , Células Cultivadas , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Quinasas Quinasa Quinasa PAM/genética , Ratones , Microglía/metabolismo , FN-kappa B/genética , Neuronas/metabolismo , Neuronas/patología , Transducción de SeñalRESUMEN
Accumulating evidence has demonstrated a possible role of mitochondrial dysfunction in migraine pathophysiology. Migraine sufferers exhibit impaired metabolic capacity, with an increased formation of reactive oxygen species (ROS). Mitochondrial dynamics and mitochondrial biogenesis are key processes regulating mitochondrial homeostasis. The aim of this study was to explore the alterations of mitochondrial regulatory networks in a rat model of migraine induced by repeated dural stimulation with inflammatory soup (IS). Ultrastructural, protein, gene and mitochondrial DNA analysis were applied to assess mitochondrial dynamics and biogenesis in trigeminal ganglion (TG) neurons. Mitochondria in TG neurons exhibited small and fragmented morphology after repeated dural stimulation. Further investigations showed that mitochondrial fission protein dynamin-related protein 1 (Drp1) was increased while mitochondrial fusion protein Mitofusin1 (Mfn1) was reduced in TG neurons. In addition, our results also presented that mitochondrial DNA copy number in TG neurons was reduced significantly, accompanied by alterations in mRNA and protein levels of regulatory factors related to mitochondrial biogenesis including peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1α) and its downstream regulators in TG neurons in the IS-induced migraine model. These findings suggest that the mitochondrial dynamic regulatory networks are maladjusted in TG neurons in a rat model of migraine. Regulation of mitochondrial dynamics and biogenesis signaling may indicate a new mitochondria-targeted therapeutic strategy for migraine.