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miR-330 regulates Drp-1 mediated mitophagy by targeting PGAM5 in a rat model of permanent focal cerebral ischemia.

European journal of pharmacology (2020-05-04)
Wei Zuo, Feng Yan, Zhenyu Liu, Bo Zhang
ABSTRACT

Growing evidence have suggested that mitophagy could exert a neuroprotective role in brain ischemia by removing the damaged mitochondria. However the upstream mechanisms of mitophagy are remain unclear. We previously observed a decrease of miR-330 in a miRNA profile of plasma from patients within 3 h after a stroke. Our study further focused on the role and mechanism of miR-330 in mitophagy induced by hypoxia-ischemia (H/I) in rats. Cerebral ischemia model in rats was made with permanent middle cerebral artery occlusion (pMCAO). In vitro, ischemic model in primary neurons was established with oxygen-glucose deprivation. Various methods, including TTC staining, immunofluorescence staining, Western blot, ELISA, flow cytometry, and transmission electron microscopy were used to clarify the role of miR-330 after H/I, and whether miR-330/phosphoglycerate mutase family member 5 (PGAM5) axis could regulate dynamin-related protein 1 (Drp-1) mediated mitophagy. MiR-330 levels decreased both in rat plasma and in ipsilateral brain tissues after H/I. Pretreating animals with miR-330 antagomir could decrease cerebral infarction, edema, mortality, and apoptosis after 6-h pMCAO. PGAM5 was validated as a target of miR-330. MiR-330 agomir and antagomir transfection respectively decreased and increased the PGAM5 protein expression. MiR-330 could down-regulate mitophagy by inhibiting PGAM5-induced Drp1 dephosphorylation, thus reducing the recruitment of Drp1 to mitochondrial outer membrane and Drp1-mediated mitophagy after H/I. Our results suggest a role of miR-330 in regulating mitophagy. Our study suggested a novel miR-based intervention strategy for stroke.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
2,3,5-トリフェニルテトラゾリウムクロリド, ≥98.0% (HPLC)
Sigma-Aldrich
抗LC3B ウサギ宿主抗体, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
MISSION® esiRNA, targeting human PGAM5