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HIF?1? attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia?reperfusion injury in a rat MCAO model.

ABSTRACT: Hypoxia?inducible factor?1? (HIF?1?) is a key transcriptional factor in response to hypoxia and is involved in ischemic stroke. In the present study, the potential for HIF?1? to inhibit neuronal apoptosis through upregulating erythropoietin (EPO) was investigated in a transient middle cerebral artery occlusion (tMCAO) rat stroke model. For this purpose, a recombinant adenovirus expressing HIF?1? was engineered (Ad?HIF?1?). Control adenovirus (Ad group), Ad?HIF?1? (Ad?HIF?1? group) or Ad?HIF?1? in addition to erythropoietin mimetic peptide?9 (EMP9), an EPO?receptor (?R) antagonist (Ad?HIF?1?+EMP9 group), were used for an intracranial injection into rat ischemic penumbra 1 h following MCAO. All rats demonstrated functional improvement following tMCAO, while the improvement rate was faster in rats treated by Ad?HIF?1? compared with all other groups. The EPO?R inhibitor partially reversed the benefits of Ad?HIF?1?. Apoptosis induced by tMCAO was significantly inhibited by Ad?HIF?1? (P<0.05). The expression of HIF?1?, evaluated by immunohistochemistry either in neurons or astrocytes, was upregulated by Ad?HIF?1?. Both EPO mRNA and protein expression were increased by Ad?HIF?1?, however, there was no significant change of EPO?R either on an mRNA level or protein level. Furthermore, EMP9 did not change the EPO expression which was upregulated by Ad?HIF?1?. Activated caspase 3 in neurons was suppressed by Ad?HIF?1?. Activated caspase 3 downregulated by HIF?1? was partially blocked by EMP9. Altogether, the present data demonstrated that HIF?1? attenuates neuronal apoptosis partially through upregulating EPO following cerebral ischemia in rat. Thus, upregulating HIF?1? subsequent to a stroke may be a potential treatment for ischemic stroke.

SUBMITTER: Li J

PROVIDER: S-EPMC7053873 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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HIF‑1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia‑reperfusion injury in a rat MCAO model.

Li Jun J Tao Tao T Xu Jian J Liu Zhi Z Zou Zhehua Z Jin Minglu M

International journal of molecular medicine 20200128 4

Hypoxia‑inducible factor‑1α (HIF‑1α) is a key transcriptional factor in response to hypoxia and is involved in ischemic stroke. In the present study, the potential for HIF‑1α to inhibit neuronal apoptosis through upregulating erythropoietin (EPO) was investigated in a transient middle cerebral artery occlusion (tMCAO) rat stroke model. For this purpose, a recombinant adenovirus expressing HIF‑1α was engineered (Ad‑HIF‑1α). Control adenovirus (Ad group), Ad‑HIF‑1α (Ad‑HIF‑1α group) or Ad‑HIF‑1α i ...[more]

PMID: 32124933

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Project description:Ischemic stroke is an acute and severe neurological disease with high mortality and disability rates worldwide. Polymerase I and transcript release factor (PTRF) plays a pivotal role in regulating cellular senescence, glucose intolerance, lipid metabolism, and mitochondrial bioenergetics, but its mechanism, characteristics, and functions in neuronal cells following the cerebral ischemia-reperfusion (I/R) injury remain to be determined. Methods: Transcription factor motif analysis, chromatin immunoprecipitation (ChIP), luciferase and co-Immunoprecipitation (co-IP) assays were performed to investigate the mechanisms of PTRF in neuronal cells after I/R injury. Lentiviral-sgRNA against PTRF gene was introduced to HT22 cells, and adeno-associated virus (AAV) encoding a human synapsin (hSyn) promoter-driven construct was transduced a short hairpin RNA (shRNA) against PTRF mRNA in primary neuronal cells and the cortex of the cerebral I/R mice for investigating the role of PTRF in neuronal damage and PLA2G4A change induced by the cerebral I/R injury. Results: Here, we reported that neuronal PTRF was remarkably increased in the cerebral penumbra after I/R injury, and HIF-1α and STAT3 regulated the I/R-dependent expression of PTRF via binding to its promoter in neuronal cells. Moreover, overexpression of neuronal PTRF enhanced the activity and stability of PLA2G4A by decreasing its proteasome-mediated degradation pathway. Subsequently, PTRF promoted reprogramming of lipid metabolism and altered mitochondrial bioenergetics, which could lead to oxidative damage, involving autophagy, lipid peroxidation, and ferroptosis via PLA2G4A in neuronal cells. Furthermore, inhibition of neuronal PTRF/PLA2G4A-axis markedly reduced the neurological deficits, cerebral infarct volumes, and mortality rates in the mice following cerebral I/R injury. Conclusion: Our results thus identify that the STAT3/HIF-1α/PTRF-axis in neurons, aggravating cerebral I/R injury by regulating the activity and stability of PLA2G4A, might be a novel therapeutic target for ischemic stroke.

Dataset Information

HIF?1? attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia?reperfusion injury in a rat MCAO model.

Publications

HIF‑1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia‑reperfusion injury in a rat MCAO model.

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