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MiR?187?3p inhibitor attenuates cerebral ischemia/reperfusion injury by regulating Seipin?mediated autophagic flux.

ABSTRACT: MicroRNAs (miRNAs/miRs) have been reported to affect ischemia/reperfusion (I/R)?induced cerebral damage. miRNAs cause post?transcriptional gene silencing by binding to the protein?coding sequence (CDS) of mRNAs. Seipin has a potential role in regulating autophagic flux. The present study investigated the involvement of miR?187?3p in Seipin expression, autophagic flux and apoptosis in vitro, as well as the underlying mechanism, using PC12 cells exposed to oxygen?glucose deprivation/reoxygenation (OGD/R), which mimicked the process of I/R. In comparison with control PC12 cells, OGD/R caused an increase in the level of miR?187?3p and a decrease in Seipin protein levels without changes in the level of Seipin mRNA. Using bioinformatics analysis, it was identified that miR?187?3p could bind to the CDS of Seipin. miR?187?3p inhibitor attenuated the reduction in Seipin protein expression in OGD/R?treated PC12 cells. Following OGD/R, autophagic flux was reduced and apoptosis was enhanced, which were attenuated by inhibition of miR?187?3p. Compared with OGD/R?treated PC12 cells, Seipin knockdown further impaired autophagic flux and promoted neuronal apoptosis, which were insensitive to inhibition of miR?187?3p. Furthermore, treatment with miR?187?3p inhibitor could decrease the infarction volume in a rat model of middle cerebral artery occlusion/reperfusion. The present findings indicated that miR?187?3p inhibitor attenuated ischemia?induced cerebral damage by rescuing Seipin expression to improve autophagic flux.

SUBMITTER: Ren Z

PROVIDER: S-EPMC7387098 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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miR‑187‑3p inhibitor attenuates cerebral ischemia/reperfusion injury by regulating Seipin‑mediated autophagic flux.

Ren Zhenkui Z Xie Peng P Lv Ju J Hu Yumei Y Guan Zhizhong Z Chen Ling L Yu Wenfeng W

International journal of molecular medicine 20200616 3

MicroRNAs (miRNAs/miRs) have been reported to affect ischemia/reperfusion (I/R)‑induced cerebral damage. miRNAs cause post‑transcriptional gene silencing by binding to the protein‑coding sequence (CDS) of mRNAs. Seipin has a potential role in regulating autophagic flux. The present study investigated the involvement of miR‑187‑3p in Seipin expression, autophagic flux and apoptosis in vitro, as well as the underlying mechanism, using PC12 cells exposed to oxygen‑glucose deprivation/reoxygenation ...[more]

PMID: 32705147

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Project description:Reperfusion injury after extended ischemia accounts for approximately 50% of myocardial infarct size, and there is no standard therapy. HDAC inhibition reduces infarct size and enhances cardiomyocyte autophagy and PGC1α-mediated mitochondrial biogenesis when administered at the time of reperfusion. Furthermore, a specific autophagy-inducing peptide, Tat-Beclin 1 (TB), reduces infarct size when administered at the time of reperfusion. However, since SAHA affects multiple pathways in addition to inducing autophagy, whether autophagic flux induced by TB maintains mitochondrial homeostasis during ischemia/reperfusion (I/R) injury is unknown. We tested whether the augmentation of autophagic flux by TB has cardioprotection by preserving mitochondrial homeostasis both in vitro and in vivo. Wild-type mice were randomized into two groups: Tat-Scrambled (TS) peptide as the control and TB as the experimental group. Mice were subjected to I/R surgery (45 min coronary ligation, 24 h reperfusion). Autophagic flux, mitochondrial DNA (mtDNA), mitochondrial morphology, and mitochondrial dynamic genes were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were treated with a simulated I/R injury to verify cardiomyocyte specificity. The essential autophagy gene, ATG7, conditional cardiomyocyte-specific knockout (ATG7 cKO) mice, and isolated adult mouse ventricular myocytes (AMVMs) were used to evaluate the dependency of autophagy in adult cardiomyocytes. In NRVMs subjected to I/R, TB increased autophagic flux, mtDNA content, mitochondrial function, reduced reactive oxygen species (ROS), and mtDNA damage. Similarly, in the infarct border zone of the mouse heart, TB induced autophagy, increased mitochondrial size and mtDNA content, and promoted the expression of PGC1α and mitochondrial dynamic genes. Conversely, loss of ATG7 in AMVMs and in the myocardium of ATG7 cKO mice abolished the beneficial effects of TB on mitochondrial homeostasis. Thus, autophagic flux is a sufficient and essential process to mitigate myocardial reperfusion injury by maintaining mitochondrial homeostasis and partly by inducing PGC1α-mediated mitochondrial biogenesis.

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MiR?187?3p inhibitor attenuates cerebral ischemia/reperfusion injury by regulating Seipin?mediated autophagic flux.

Publications

miR‑187‑3p inhibitor attenuates cerebral ischemia/reperfusion injury by regulating Seipin‑mediated autophagic flux.

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