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Micro Ribonucleic Acid 27a Aggravates Ferroptosis During Early Ischemic Stroke of Rats Through Nuclear Factor
Jing Zhang1, Hui Sun1, Lijun Zhu1
1Affiliated Hospital of North China University of Science and Technology, Tangshan, China; Key Laboratory of Medical Molecular Testing and Diagnosis in Tangshan, Tangshan, China.
Abstract:
Ischaemic stroke (IS) is characterized by high morbidity, disability and mortality and lacks effective solutions. MiRNA-27a has been implicated in ferroptosis, but evidence that miRNA-27a regulates ferroptosis in ischaemic stroke is lacking. Nrf2 could reduce brain tissue injury in ischaemic stroke and resist ferroptosis. The current study aimed to investigate the relationship between miRNA-27a/Nrf2 and ferroptosis in ischaemic stroke. In this study, IS was simulated using a permanent middle cerebral artery occlusion (pMCAO) model. The degree of brain tissue injury was assessed by conducting TTC staining and neurological function scoring. MiRNA-27a expression levels were altered via the intracerebroventricular injection of miRNA‑27a agonist or antagonist. Glutathione peroxidase 4 (GPX4), glutathione (GSH), Fe and malondialdehyde (MDA) are considered biomarkers for ferroptosis. The expression of GPX4 and Nrf2 was analysed by Western blot assay. The GSH, Fe and MDA contents were detected by detection kits. We found that the expression levels of Fe and MDA were increased, while GPX4 and GSH were decreased in the pMCAO groups compared with the control group. These results indicated that ferroptosis intensified over time during IS. In addition, the miRNA‑27a agonist significantly aggravated ferroptosis and reduced neurological function scores compared with those of the control group. Subsequently, a luciferase reporter gene system verified the targeted binding of miRNA‑27a to Nrf2. The results showed that miRNA‑27a inhibited Nrf2 in a targeted manner, which also exacerbated the extent of ferroptosis. However, the miRNA‑27a antagonist reversed the miR‑27a agonist‑mediated effects. Therefore, the present study indicated that miRNA‑27a may aggravate brain tissue ferroptosis during ischaemic stroke, potentially by inhibiting Nrf2.
Insights
MicroRNA-27a exacerbates brain tissue ferroptosis in ischaemic stroke by inhibiting Nrf2. This finding suggests a potential therapeutic target for reducing stroke-related brain damage and improving outcomes.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Ischaemic stroke (IS) presents significant morbidity and mortality with limited effective treatments.
- Ferroptosis, a regulated cell death pathway, is implicated in IS, but the role of microRNA-27a (miRNA-27a) in this process remains unclear.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) shows neuroprotective potential in IS by resisting ferroptosis.
Purpose of the Study:
- To investigate the relationship between miRNA-27a, Nrf2, and ferroptosis in the context of ischaemic stroke.
- To elucidate the mechanism by which miRNA-27a influences ferroptosis and brain injury in IS.
Main Methods:
- An ischaemic stroke model was established using permanent middle cerebral artery occlusion (pMCAO) in rats.
- miRNA-27a expression was modulated using intracerebroventricular injections of miRNA-27a agonists or antagonists.
- Ferroptosis was assessed by measuring biomarkers including glutathione peroxidase 4 (GPX4), glutathione (GSH), iron (Fe), and malondialdehyde (MDA).
- Nrf2 expression and the interaction between miRNA-27a and Nrf2 were analyzed using Western blot and a luciferase reporter gene system.
Main Results:
- Ferroptosis biomarkers (increased Fe and MDA, decreased GPX4 and GSH) were elevated in the pMCAO model, indicating ferroptosis progression over time.
- Administration of a miRNA-27a agonist worsened ferroptosis and neurological deficits.
- miRNA-27a directly targeted and inhibited Nrf2 expression.
- A miRNA-27a antagonist reversed these detrimental effects, mitigating ferroptosis and improving neurological function.
Conclusions:
- MiRNA-27a aggravates ferroptosis in brain tissue during ischaemic stroke.
- The mechanism involves the targeted inhibition of Nrf2 by miRNA-27a.
- Targeting the miRNA-27a/Nrf2 pathway may offer a novel therapeutic strategy for ischaemic stroke.
