Aims
This study's aims were two-fold, to (1) figure out the influence of lncRNA-MEG3 on neurological dysfunction subsequent to diabetic cerebral ischemic injury, (2) elucidate its potential role in mitochondria-related apoptosis via modulating the Anxa2 signaling pathway. Materials and
Background
In clinical domains, encompassing neurosurgery and macrovascular cardiac procedures, certain interventions result in cerebral ischemia- reperfusion injury (CIRI). Diabetes mellitus (DM) increases the risk of CIRI and worsens the severity of neurological impairment. It was documented that lncRNA-MEG3 contributed to the pathogenesis of CIRI. However, the pivotal significance of lncRNA-MEG3 in diabetic CIRI has never been studied. Aims: This study's aims were two-fold, to (1) figure out the influence of lncRNA-MEG3 on neurological dysfunction subsequent to diabetic cerebral ischemic injury, (2) elucidate its potential role in mitochondria-related apoptosis via modulating the Anxa2 signaling pathway. Materials and
Conclusion
The outcomes provided clinical evidence that lncRNA-MEG3 appeared as an unfavorable prognostic factor for diabetic CIRI and revealed that lncRNA-MEG3 knockdown could be protective against diabetic CIRI-induced mitochondria-related apoptosis through modulating Anxa2 binding to Akt in mitochondria.
Methods
We mainly collected plasma from clinical patients to measure the expression of lncRNA-MEG3, and explored the molecular mechanism of lncRNA-MEG3 in CIRI combined with DM by immunofluorescence, western blot, co-ip and other molecular biology experiments in rat MACO+DM model and cellular OGD/R+HG model.
Results
LncRNA-MEG3 expression in DM+AIS cases was remarkably higher than that in cases with AIS and healthy controls. Moreover, lncRNA-MEG3 expression was strongly linked to the National Institutes of Health Stroke Scale (NIHSS) score. Additionally, the findings unveiled that lncRNA-MEG3 depletion alleviated neurological impairments following CIRI in diabetic rats, and cellular death resulted from Oxygen-glucose deprivation (OGD) plus hyperglycemic reperfusion in rat brain microvascular endothelial cells (RBMVECs) that was concomitant with the increased phosphorylation of Annexin A2 (Anxa2) at Tyr23. Meanwhile, over expression of Anxa2, identified as a lncRNA-MEG3-associated mitochondrial protein, remarkably suppressed mitochondria-derived apoptosis. Importantly, lncRNA-MEG3 knockdown enhanced the mitochondrial translocation of Anxa2 via promoting its phosphorylation at Tyr23 in OGD+HG-treated RBMVECs. Furthermore, Anxa2 enhanced Akt phosphorylation at Ser473 and bound to Akt in mitochondria, which was involved in lncRNA-MEG3 depletion-induced neuroprotection. However, lncRNA-MEG3 mobilized to mitochondria in a Plectin-dependent manner and subsequently impeded the interaction between p-Anxa2 and p-Akt.