title: MicroRNA-682-mediated downregulation of PTEN in intestinal epithelial cells ameliorates intestinal ischemia-reperfusion injury.
abstract: Intestinal ischemia-reperfusion (I/R) injury causes inflammation and tissue damage and contributes to high morbidity and mortality, but the underlying mechanism remains elusive and effective therapies are still lacking. We report here a critical role of the microRNA 682 (miR-682) as a key regulator and therapeutic target in intestinal I/R injury. MiR-682 was markedly induced in intestinal epithelial cells (IECs) during intestinal ischemia in mice and in the human colonic epithelial cells during hypoxia, but was undetected rapidly after intestinal reperfusion in IEC of mice. MiR-682 induction during hypoxia was modulated by hypoxia-inducible factor-1α (HIF-1α). On lentivirus-mediated miR-682 overexpression in vivo during intestinal reperfusion or miR-682 mimic transfection in vitro during hypoxia, miR-682 decreased the expression of phosphatase and tensin homolog (PTEN) and subsequently activated nuclear translocation of nuclear factor kappa B (NF-κB) p65. Consequently, NF-κB activation by miR-682-mediated PTEN downregulation prevented reactive oxygen species (ROS) induction, inflammatory reaction, mitochondrial-mediated apoptosis and IEC apoptosis. The effect of miR-682-mediated PTEN/NF-κB pathway on IECs resulted in protection against intestinal I/R injury in mice. However, NF-κB chemical inhibitor reversed miR-682-mediated decreased PTEN expression, ROS induction, inflammation and IEC apoptosis. Collectively, these results identify a novel miR-682/PTEN/NF-κBp65 signaling pathway in IEC injury induced by I/R that could be targeted for therapy.
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou 510360, China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Guangzhou 510360, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: D
authors.initials: D
authors.lastname: Zou
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Emergence Medicine, Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhan
mesh_terms: D000818:Animals; D017209:Apoptosis; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D016019:Survival Analysis; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D009570:Nitriles; D009942:Organometallic Compounds; D010618:Phenanthrolines; D017382:Reactive Oxygen Species; C498144:Rela protein, mouse; D013450:Sulfones; D051996:Transcription Factor RelA; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse