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EGR2 affects mixed stroke repair through BNIP3L-mediated microglial mitophagy
Xiujun Zhang1,2, Bensi Zhang1,2, Chun Shi2,3
1Department of Anatomy, Faculty of Medicine, Chiang Mai University, Inthawarorot Road, Chiang Mai, Thailand.
Abstract:
Mixed stroke, also known as hemorrhagic infarction or infarction with hemorrhage, presents as a cerebral infarction combined with intracerebral hemorrhage (ICH) on computed tomography (CT) brain scans. ICH is a brain parenchymal hemorrhage caused by the loss of vascular integrity, which can lead to permanent disability or death. The early growth response 2 (EGR2) gene has been studied in a variety of brain diseases. However, effective treatments are still lacking.
Methods:
In this study, a cell model was constructed using oxyhemoglobin (OxyHb), and cell viability was detected using CCK-8. The mitochondrial membrane potential was measured using a mitochondrial membrane potential detection kit. Protein stress was used to assess the expression of EGR2, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L or BNIP3L/NIX), and autophagy-related proteins. RT-qPCR detected the expression of EGR2 and BNIP3L mRNA. Microtubule-associated protein 1 A/1B-light chain 3 (LC3) expression was detected by immunofluorescence.
Results:
This study found that OxyHb reduced microglial viability in a concentration-dependent manner, and 20 μM OxyHb produced the most robust effect and was selected for subsequent experiments. In the cell model, the membrane potential of microglia decreased, and the fluorescence intensities of autophagy-related proteins (ATG7, LC3 II/LC3 I, and P62) and LC3 were inhibited. Over-expression-EGR2 (oe-EGR2) can increase the membrane potential of microglia and promote the fluorescence intensity of autophagy-related proteins (ATG7, LC3 II/LC3 I, and P62) and LC3. Mitochondrial division inhibitor-1 (Mdivi-1) and sh-BNIP3L could reverse the effect of oe-EGR2.
Conclusion:
EGR2 promotes microglial mitophagy by upregulating BNIP3L, thereby alleviating ICH.
Insights
Early Growth Response 2 (EGR2) gene promotes microglial mitophagy, a process that helps clear damaged mitochondria. This mechanism alleviates intracerebral hemorrhage (ICH) by upregulating BNIP3L, offering potential therapeutic insights.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Intracerebral hemorrhage (ICH) is a severe type of stroke with limited treatment options.
- The Early Growth Response 2 (EGR2) gene's role in brain diseases is under investigation.
- Understanding the molecular mechanisms of ICH is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of EGR2 in microglial response to intracerebral hemorrhage (ICH).
- To explore the potential of EGR2 as a therapeutic target for ICH.
- To elucidate the molecular pathways involved in EGR2-mediated protection against ICH.
Main Methods:
- A cell model of ICH was established using oxyhemoglobin (OxyHb).
- Cell viability, mitochondrial membrane potential, and protein/mRNA expression (EGR2, BNIP3L, LC3, ATG7, P62) were assessed.
- Immunofluorescence and RT-qPCR were used to analyze autophagy and protein levels.
Main Results:
- OxyHb reduced microglial viability and mitochondrial membrane potential.
- Overexpression of EGR2 (oe-EGR2) increased microglial membrane potential and promoted autophagy-related protein expression.
- EGR2 promotes microglial mitophagy by upregulating BNIP3L, which was confirmed by the reversal effects of Mdivi-1 and sh-BNIP3L.
Conclusions:
- EGR2 plays a protective role in ICH by enhancing microglial mitophagy.
- Upregulation of BNIP3L by EGR2 is a key mechanism in mitigating ICH-induced damage.
- Targeting EGR2-mediated mitophagy presents a potential therapeutic strategy for intracerebral hemorrhage.
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