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Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the
Qiang Zhang1,2, Haohong Zhan3,2, Cong Liu1,2
1Department of Emergency Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Abstract:
Substantial morbidity and mortality are associated with postcardiac arrest brain injury (PCABI). MicroRNAs(miRNAs) are essential regulators of neuronal metabolism processes and have been shown to contribute to alleviated neurological injury after cardiac arrest. In this study, we identified miRNAs related to the prognosis of patients with neurological dysfunction after cardiopulmonary resuscitation based on data obtained from the Gene Expression Omnibus (GEO) database. Then, we explored the effects of miR-483-5p on mitochondrial biogenesis, mitochondrial-dependent apoptosis, and oxidative stress levels after ischemia‒reperfusion injury in vitro and in vivo. MiR-483-5p was downregulated in PC12 cells and hippocampal samples compared with that in normal group cells and hippocampi. Overexpression of miR-483-5p increased the viability of PC12 cells after ischemia‒reperfusion injury and reduced the proportion of dead cells. A western blot analysis showed that miR-483-5p increased the protein expression of PCG-1, NRF1, and TFAM and reduced the protein expression of Bax and cleaved caspase 3, inhibiting the release of cytochrome c from mitochondria and alleviating oxidative stress injury by inhibiting the production of ROS and reducing MDA activity. We confirmed that miR-483-5p targeted TNFSF8 to regulate the AMPK/JNK pathway, thereby playing a neuroprotective role after cardiopulmonary resuscitation. Hence, this study provides further insights into strategies for inhibiting neurological impairment after cardiopulmonary resuscitation and suggests a potential therapeutic target for PCABI.
Insights
MicroRNAs (miRNAs) protect the brain after cardiac arrest. This study shows miR-483-5p enhances cell survival and reduces injury by regulating mitochondrial function and oxidative stress, offering a potential therapeutic target for postcardiac arrest brain injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Postcardiac arrest brain injury (PCABI) leads to significant morbidity and mortality.
- MicroRNAs (miRNAs) are key regulators of neuronal metabolism and neurological injury.
- Identifying prognostic miRNAs is crucial for understanding PCABI outcomes.
Purpose of the Study:
- To identify miRNAs associated with neurological dysfunction prognosis after cardiopulmonary resuscitation (CPR).
- To investigate the neuroprotective effects of miR-483-5p in ischemia-reperfusion injury.
- To elucidate the mechanisms underlying miR-483-5p's action on mitochondrial function, apoptosis, and oxidative stress.
Main Methods:
- Bioinformatic analysis of Gene Expression Omnibus (GEO) database for miRNA identification.
- In vitro and in vivo experiments using PC12 cells and hippocampal samples.
- Western blot analysis to assess protein expression and molecular pathway activation.
Main Results:
- miR-483-5p was downregulated in PC12 cells and hippocampi post-ischemia-reperfusion.
- Overexpression of miR-483-5p enhanced cell viability and reduced cell death.
- miR-483-5p promoted mitochondrial biogenesis, inhibited apoptosis, and reduced oxidative stress by targeting TNFSF8 and regulating the AMPK/JNK pathway.
Conclusions:
- miR-483-5p plays a significant neuroprotective role after CPR.
- Targeting miR-483-5p offers a potential therapeutic strategy for mitigating neurological impairment in PCABI.
- This study provides insights into novel therapeutic targets for PCABI.
