MicroRNA-29a-5p attenuates hemorrhagic transformation and improves outcomes after mechanical reperfusion for acute ischemic stroke.

BACKGROUND: Hemorrhage transformation (HT) following endovascular reperfusion treatment is associated with worse clinical outcomes in acute ischemic stroke patients. MicroRNA (miR) modulates several aspects of cerebral ischemia-reperfusion injury, including blood-brain barrier (BBB) integrity, inflammation, oxidative stress, and apoptosis, significantly impacting cerebral recovery and function. This study investigated the role of astrocytic miR-29a-5p in HT in the transient middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation reoxygenation (OGD/R) model of astrocytes. METHODS: MiR-29a-5p expression in the OGD/R astrocyte model was assessed. The astrocyte injury, the expression of A1 and A2 phenotypes of reactive astrocytes, and the regulation of miR-29a-5p target genes were evaluated after the miR-29a-5p intervention. A mechanical reperfusion-induced HT model was established in hyperglycemic rats using 5-h MCAO following reperfusion at 6 h. MiR-29a-5p agomir was administered intravenously before reperfusion. Infarct volume, HT, BBB damage, neurological score, the expression of miR-29a-5p, and its target genes were evaluated. RESULTS: MiR-29a-5p expression decreased in OGD/R-treated astrocytes and the peri-infarction tissue and blood of the MCAO model. Elevating miR-29a-5p levels reduced astrocyte injury, suppressed neurotoxic A1 astrocyte markers (C3, Fkbp5, and Serping1), while enhanced neuroprotective A2 astrocyte markers (S100a10 and Emp1) in the OGD/R and MCAO models. Intravenous administration of miR-29a-5p agomir increased the expression of miR-29a-5p and reduced infarct volume, reperfusion-induced HT, and BBB breakdown after ischemia, improving neurological outcomes in the MCAO model. Overexpression of miR-29a-5p effectively suppressed the expression of its direct target genes, glycogen synthase kinase 3 beta and aquaporin 4 in the OGD/R and MCAO models. CONCLUSIONS: MiR-29a-5p alleviates astrocyte injury and regulates A1 and A2 astrocyte markers, glycogen synthase kinase 3 beta, and aquaporin 4 in astrocytes subjected to ischemia-reperfusion injury. Astrocytic miR-29a-5p may be a protective target for reducing HT and improving outcomes following mechanical reperfusion in acute ischemic stroke.