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 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.

MiR-29a and miR-652 Attenuate Liver Fibrosis by Inhibiting the Differentiation of CD4+ T Cells

“…It has been widely reported that the dysregulated miRNAs could result in multiple diseases, previous studies have indicated that miRNAs control cellular processes, such as cell proliferation, oxidative stress, inflammatory reaction, as well as tumor growth (Cai et al, 2016;Baker et al, 2016;Hill et al, 2015). The analysis of miRNA on liver diseases have been documented several years before, the down-regulations of miR-150 and miR-194 were demonstrated to lead to severe liver fibrosis (Venugopal et al, 2010), while the over-expression of miR-494 acted as an oncogenicmiRNA that regulated liver tumorgensis (Lim et al, 2014).…”

Lung ageing and COPD: is there a role for ageing in abnormal tissue repair?

“…The NAD + -dependent Class III protein deacetylases known as the Sirtuin family are frequently described as anti-ageing enzymes [93]. The fact that SIRT1 and -6 have been shown to be decreased in peripheral lung tissue (and SIRT1 also in serum) of COPD patients compared to controls suggests age-associated acetylation differences in COPD [94,95]. BAKER et al [94] postulate that the reduced expression of both Sirtuins is regulated by the microRNA MiR-34a, a small endogenous noncoding RNA, which appears to be increased in COPD patients compared to controls.…”

Genetics Association and Epigenetic Changes in COPD

“…Recently, we proposed that inhibition of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes and survival of inflammatory cells associated with inflammation in COPD. We demonstrated for the first time a known BET inhibitor, JQ1, showed a difference potency for inhibitions of IL6 in human peripheral blood mononuclear cells (PBMC) from normal or COPD in comparison to alveolar macrophages stimulated with LPS [31]. Furthermore, BET inhibitor JQ1 attenuated multiple genes, including pro-inflammatory cytokines and genes regulating innate and adaptive immune cells.…”

“…SIRT1 is reported to inhibits autophagy, cellular senescence, fibrosis, and inflammation by deacetylation of target proteins using NAD + as co-substrate. Similarly SIRT6 have also been shown to be associated with reduction-oxidation reaction (redox) state and inhibits cellular senescence and fibrosis [31]. Therefore, pathways associated with activation of SIRT1 and SIRT6 are an attractive approach for novel therapeutic targets for COPD.…”

“…In the preclinical models efficacy of non-selective activators of SIRT1 using the pharmacological activator SRT1720 has been demonstrated Activation of SIRT1 via SRT2172 inhibits pulmonary neutrophil accumulation, and completely restored exercise tolerance and the fall in oxygen saturation and protects against cigarette smoke (CS) and elastase-induced emphysema in mice [32]. Furthermore, resveratrol, a substance shown to activate SIRT1 attenuates cigarette smoke extract (CSE)-mediated glutathione depletion through reversing CSE-mediated NRF2 carbonylation in lung epithelium cell line, A549 cells [31,32]. Due to a recent study in human airway smooth muscle cells, resveratrol is suggested as an anti-inflammatory therapy alternative to corticosteroids in COPD, particularly in COPD exacerbations [33].…”