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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 H2O2 was 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.

Original publication

DOI

10.1038/srep35871

Type

Journal article

Journal

Sci Rep

Publication Date

21/10/2016

Volume

6

Keywords

3' Untranslated Regions, Antagomirs, Cell Line, Cellular Senescence, DNA-Binding Proteins, Down-Regulation, Epithelial Cells, Humans, Hydrogen Peroxide, Lung, MicroRNAs, Nuclear Proteins, Oxidative Stress, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Pulmonary Disease, Chronic Obstructive, RNA, Messenger, RNA-Binding Proteins, Sirtuin 1, Sirtuins, Sputum, Up-Regulation