title: Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells.
abstract: Sirtuin-1 (SIRT1) and SIRT6, NAD+-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases.
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: J R
authors: JR
authors: Baker
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: C
authors: C
authors: Vuppusetty
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: T
authors: T
authors: Colley
authors: 3rd Respiratory Medicine Department, Sismanogleio Hospital, Marousi Athens Greece.
authors: Andriana I
authors: AI
authors: Papaioannou
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: P
authors: P
authors: Fenwick
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: Louise
authors: L
authors: Donnelly
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: K
authors: K
authors: Ito
authors: Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY, U.K.
authors: P J
authors: PJ
authors: Barnes
mesh_terms: D020413:3' Untranslated Regions; D000070416:Antagomirs / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008168:Lung / Q000378:metabolism; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013183:Sputum / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D000070416:Antagomirs; D004268:DNA-Binding Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C110225:PPP1R10 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C516592:SIRT6 protein, human; D056564:Sirtuin 1; D037761:Sirtuins