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Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area
Published on: February 2, 2017
MicroRNAs Associated with Parenchymal Hematoma After Endovascular Mechanical Reperfusion for Acute Ischemic Stroke in
Jin-Kun Zhuang1,2, Zhong-Run Huang1,2,3, Wang Qin1,2,3
1Department of Neurosurgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Abstract:
Background/Objectives: Hemorrhagic transformation after endovascular thrombectomy predicts poor outcomes in acute ischemic stroke with large-vessel occlusion. The roles of microRNAs (miRNAs) in the pathogenesis of parenchymal hematoma (PH) after endovascular thrombectomy still remain unclear. This study aimed to investigate the miRNA and mRNA regulatory network associated with PH after mechanical reperfusion in an animal stroke model and an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Methods: Twenty-five miRNAs were assessed in a mechanical reperfusion-induced hemorrhage transformation model in rats under hyperglycemic conditions receiving 5 h middle cerebral artery occlusion. The differentially expressed miRNAs associated with PH were assessed in a neuron, astrocyte, microglia, brain microvascular endothelial cell (BMEC), and pericyte model of OGD/R. The predicted target genes of the differentially expressed miRNAs were further assessed in the animal model. The miRNA-mRNA regulatory network of PH was established. Results: Thirteen down-regulated miRNAs (miRNA-29a-5p, miRNA-29c-3p, miRNA-126a-5p, miRNA-132-3p, miRNA-136-3p, miRNA-142-3p, miRNA-153-5p, miRNA-218a-5p, miRNA-219a-2-3p, miRNA-369-5p, miRNA-376a-5p, miRNA-376b-5p, and miRNA-383-5p) and one up-regulated miRNA (miRNA-195-3p) were found in the rat peri-infarct with PH after mechanical reperfusion. Of these 14 PH-related miRNAs, 10 were significantly differentially expressed in at least two of the five neuron, astrocyte, microglia, BMEC, and pericyte models after OGD/R, consistent with the animal stroke model results. Thirty-one predicted hub target genes were significantly differentially expressed in the rat peri-infarct with PH after mechanical reperfusion. Forty-nine miRNA-mRNA regulatory axes of PH were revealed, and they were related to the mechanisms of inflammation, immunity, oxidative stress, and apoptosis. Conclusions: Fourteen miRNAs were associated with PH after mechanical reperfusion in the rat stroke and the OGD/R models. Simultaneously differentially expressed miRNAs and related genes in several cells of the neurovascular unit may serve as valuable targets for PH after endovascular thrombectomy in acute ischemic stroke.
Insights
Hemorrhagic transformation after stroke treatment is linked to specific microRNAs (miRNAs) and their target genes. Identifying these molecular players could lead to new therapies for preventing bleeding after endovascular thrombectomy.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- Hemorrhagic transformation (PH) post-endovascular thrombectomy for acute ischemic stroke correlates with poor patient outcomes.
- The precise role of microRNAs (miRNAs) in the development of PH following mechanical reperfusion remains largely uncharacterized.
Purpose of the Study:
- To elucidate the miRNA and messenger RNA (mRNA) regulatory network implicated in parenchymal hematoma (PH) formation after mechanical reperfusion.
- To investigate these regulatory networks in both an established animal stroke model and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) cellular model.
Main Methods:
- Assessed miRNA expression in a rat model of mechanical reperfusion-induced hemorrhagic transformation under hyperglycemic conditions.
- Evaluated differentially expressed miRNAs in neuronal, astrocytic, microglial, brain microvascular endothelial cell (BMEC), and pericyte OGD/R models.
- Identified and analyzed predicted miRNA target genes within the animal model to construct a comprehensive miRNA-mRNA regulatory network for PH.
Main Results:
- Identified 14 differentially expressed miRNAs (13 down-regulated, 1 up-regulated) in the rat peri-infarct region with PH.
- Confirmed differential expression of 10 of these miRNAs in at least two OGD/R cellular models, aligning with animal study findings.
- Revealed 31 predicted hub target genes and 49 miRNA-mRNA regulatory axes associated with PH, linked to inflammation, immunity, oxidative stress, and apoptosis pathways.
Conclusions:
- Fourteen specific miRNAs are significantly associated with PH following mechanical reperfusion in both animal and cellular stroke models.
- The identified differentially expressed miRNAs and their related genes within the neurovascular unit present potential therapeutic targets for mitigating PH after endovascular thrombectomy in acute ischemic stroke.
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