TY - JOUR T1 - Sirtuins, the anti-ageing molecules, regulate anti-oxidant capacity via FoxO3 activity in monocytic cell line JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - p3860 AU - Laura Nunez Naveira AU - Nicolas Mercado AU - Kazuhiro Ito Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/p3860.abstract N2 - Chronic Obstructive Pulmonary Disease (COPD) is characterized by high levels of oxidative stress due to reduced anti-oxidative stress capacity, leading to an increase of endogenous oxidative stress. Sirtuins, type III histone deacetylases,and FoxO3 are reported to participate of the oxidative stress defence and also the levels of SIRT1 and 6 are reduced in COPD samples (Nakamaru Y, FASEB J, 2009).Aims: To evaluate the effects of sirtuin inhibition and oxidative stress on the expression of several FoxO3-responsive genes, such as catalase, superoxide dismutase (MnSOD) and thioredoxin (TXN) and also on FoxO3 binding activity.Methods: THP-1 monocytic cells were treated with a sirtuin inhibitor (sirtinol) and hydrogen peroxide (H202) as oxidative stress reagent. SIRT1, 2 and 6 were knocked down using RNA interference. The mRNA levels of catalase, MnSOD and TXN were measured by RT-PCR and normalized against GNB2L1. FoxO3 binding capacity was measured by ELISA.Results: FoxO3 nuclear localization was not affected by H202 or sirtinol, but the activity binding was increased with oxidative stress. This activation was abrogated with a pretreatment of sirtinol. H202 increased mRNA levels of MnSOD (25%) and TNX (70%), and again sirtinol pretreatment led to the abrogation of this activation. SIRT1, 2 and 6 were knocked down by 50% at protein level. TXN activation by H202 was blocked in every sirtuin knock down.Discussion: Defect of sirtuin expression may cause a reduction of the anti-oxidative stress capacity by regulating mRNA levels of TXN through FoxO3 in COPD. These results highlight the important role of sirtuins and its possible use as therapeutic target for treating COPD. ER -