Transcription Factor E2F1 Aggravates Neurological Injury in Ischemic Stroke via microRNA-122-Targeted Sprouty2
Yunxia Wu1, Zhiqiang Gao1, Jiang Zhang1
1Department of Neurology, Linyi Central Hospital, Linyi, Shandong 276400, People's Republic of China.
Background:
It has been documented that microRNAs (miRs) assume a pivotal role in the development of ischemic stroke (IS). However, it remains poorly identified about the role of miR-122 in IS. Herein, this study was intended to explore the mechanism of E2F1-orchestrated miR-122 in IS.
Patients And Methods:
E2F1, miR-122, and SPRY2 expression in serum from patients with IS and oxygen-glucose deprivation (OGD)-treated N2a cells was detected by RT-qPCR. After gain- and loss-of-function approaches in OGD-induced N2a cells, GAFP staining, flow cytometry, and Western blot analysis were adopted to assess neuronal viability, cell cycle and apoptosis, and expression of apoptosis- and autophagy-related proteins, respectively. Meanwhile, mice with IS were induced, in which E2F1, miR-122, and SPRY2 were overexpressed, followed by evaluation of neurological deficit and cerebral infarction area. The MAPK pathway activity in tissues of mice and cells was determined.
Results:
miR-122 was down-regulated, and E2F1 and SPRY2 were up-regulated in IS patients and OGD-induced N2a cells. E2F1 inhibited miR-122 transcription, while miR-122 targeted SPRY2. Overexpression (OE) of miR-122 or down-regulation of E2F1 or SPRY2 increased viability, but decreased apoptosis, cell cycle arrest, and autophagy in OGD-induced N2a cells. In IS mice, the neurological deficit score and cerebral infarction area were elevated, which was aggravated by up-regulating E2F1 or SPRY2 but attenuated by overexpressing miR-122. E2F1/miR-122/SPRY2 axis mediated the MAPK pathway in vivo and in vitro.
Conclusion:
Collectively, E2F1 reduced miR-122 transcription to up-regulate SPRY2, which inactivated MAPK pathway and promoted neurological deficit in IS.
Insights
E2F1 downregulates miR-122, increasing SPRY2 and promoting neurological deficits in ischemic stroke (IS). Restoring miR-122 levels can mitigate IS progression by targeting SPRY2 and the MAPK pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRs) are implicated in ischemic stroke (IS) pathogenesis.
- The specific role of miR-122 in IS requires further elucidation.
- This study investigates the mechanism of E2F1-regulated miR-122 in IS.
Purpose of the Study:
- To explore the regulatory mechanism of E2F1-orchestrated miR-122 in ischemic stroke.
- To determine the role of the E2F1/miR-122/SPRY2 axis in IS pathophysiology.
- To investigate the impact of this axis on the MAPK pathway.
Main Methods:
- Detected E2F1, miR-122, and SPRY2 expression in IS patients and OGD-treated N2a cells using RT-qPCR.
- Utilized gain- and loss-of-function studies in vitro and in vivo models of IS.
- Assessed neuronal viability, cell cycle, apoptosis, protein expression, neurological deficit, and cerebral infarction area.
Main Results:
- miR-122 was downregulated, while E2F1 and SPRY2 were upregulated in IS patients and cells.
- E2F1 inhibited miR-122 transcription; miR-122 targeted SPRY2.
- Modulating the E2F1/miR-122/SPRY2 axis affected neuronal viability, apoptosis, cell cycle, and MAPK pathway activity in vitro and in vivo.
Conclusions:
- E2F1 reduces miR-122 transcription, leading to SPRY2 upregulation.
- This axis inactivates the MAPK pathway, exacerbating neurological deficits in IS.
- Targeting the E2F1/miR-122/SPRY2 pathway offers potential therapeutic strategies for IS.
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