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 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.
Highlights
Oxidative stress is a result of an imbalance between the production of free radicals and anti-oxidants, which detoxify or counteract the free-radicals’ harmful effects
It is well documented that a decrease in the mRNA levels of SIRT1 and SIRT6 is found in patients with chronic obstructive pulmonary disease (COPD), with no proposed mechanism[12,22]
MiR-34a gene expression showed a trend towards an increase with age, in agreement others previous finding in aged mice[24]. This induction seemed to be selective for miR-34a as the other two closely related miRNA-34 family members, miRNA-34b and miRNA-34c, showed a trend towards reduced expression in COPD (Fig. 1C,D). Both have previously been shown to be down-regulated in patients with COPD, with significance being associated with emphysema severity[35]
Summary
Oxidative stress is a result of an imbalance between the production of free radicals and anti-oxidants, which detoxify or counteract the free-radicals’ harmful effects. P16 and p21, which are cyclin-dependent kinase inhibitor proteins and induce G1 stage cell cycle arrest[19], are well-known markers of senescence and have been shown to be elevated in expression in cells taken from COPD patients[13,20]. In this regard, SIRT1 has been implicated in the regulation of both senescence and the expression of p16 and p2114. As well as regulating the expression of the SIRT1 and SIRT6, miR-34a has been shown to directly regulate the expression of Protein phosphatase-1 nuclear targeting subunit (PNUTS)[24]; this protein is associated with ageing and regulates several pathways involved in accelerated aging, including the regulation of telomere length, DNA damage responses and cell cycle progression[24,34]
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