Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis

https://doi.org/10.4081/ejh.2021.3224

Authors

  • Cheng Chen Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
  • Yan Huang Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
  • Pingping Xia Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China.
  • Fan Zhang Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China.
  • Longyan Li Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China.
  • E Wang Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China. https://orcid.org/0000-0001-9463-9769
  • Qulian Guo Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China.
  • Zhi Ye | yezhi523@csu.edu.cn Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China. https://orcid.org/0000-0001-5785-8786

Abstract

Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. LncRNA Meg3 has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of Meg3 in diabetic brain ischemic injury remain unclear. In this study, rat brain microvascular endothelial cells (RBMVECs) were exposed to 6 h of oxygen and glucose deprivation (OGD), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased Meg3 expression occurred after the injury induced by OGD combined with hyperglycemia. However, all ferroptotic events were reversed with the treatment of Meg3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of Meg3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the reintroduction of p53 into cells silenced by Meg3. Finally, chromatin immunoprecipitation assay uncovered that p53 was bound to GPX4 promoter. Altogether, these data revealed that, by modulating GPX4 transcription and expression, the Meg3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic reperfusion.

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Published
2021-09-30
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Keywords:
lncRNA-MEG3, p53, ferroptosis, ischemia, GPX4, OGD, hyperglycemia
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How to Cite
Chen, C., Huang, Y., Xia, P., Zhang, F., Li, L., Wang, E., Guo, Q., & Ye, Z. (2021). Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis. European Journal of Histochemistry, 65(3). https://doi.org/10.4081/ejh.2021.3224