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  • 标题:Differential Regulation of mTOR Complexes with miR-302a Attenuates Myocardial Reperfusion Injury in Diabetes
  • 本地全文:下载
  • 作者:Arun Samidurai ; Ramzi Ockaili ; Chad Cain
  • 期刊名称:iScience
  • 印刷版ISSN:2589-0042
  • 出版年度:2020
  • 卷号:23
  • 期号:12
  • 页码:1-30
  • DOI:10.1016/j.isci.2020.101863
  • 语种:English
  • 出版社:Elsevier
  • 摘要:SummaryPersistent activation of mTOR (mammalian target of rapamycin) in diabetes increases the vulnerability of the heart to ischemia/reperfusion (I/R) injury. We show here that infusion of rapamycin (mTOR inhibitor) at reperfusion following ischemia reduced myocardial infarct size and apoptosis with restoration of cardiac function in type 1 diabetic rabbits. Likewise, treatment with rapamycin protected hyperglycemic human-pluripotent-stem-cells-derived cardiomyocytes (HG-hiPSC-CMs) following simulated ischemia (SI) and reoxygenation (RO). Phosphorylation of S6 (mTORC1 marker) was increased, whereas AKT phosphorylation (mTORC2 marker) and microRNA-302a were reduced with concomitant increase of its target, PTEN, following I/R injury in diabetic heart and HG-hiPSC-CMs. Rapamycin inhibited mTORC1 and PTEN, but augmented mTORC2 with restoration of miRNA-302a under diabetic conditions. Inhibition of miRNA-302a blocked mTORC2 and abolished rapamycin-induced protection against SI/RO injury in HG-hiPSC-CMs. We conclude that rapamycin attenuates reperfusion injury in diabetic heart through inhibition of PTEN and mTORC1 with restoration of miR-302a-mTORC2 signaling.Graphical AbstractDisplay OmittedHighlights•miR-302a and AKT phosphorylation are suppressed in post-ischemic diabetic heart•Negative regulator of insulin signaling, PTEN, is induced after ischemia reperfusion•miRNA-302a-mimic abolishes ischemic injury in hyperglycemic human iPS cardiocytes•Rapamycin treatment restores miR-302a-mTORC2 cardioprotective signaling in diabetesHuman Metabolism; Molecular Biology
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