PT  - JOURNAL ARTICLE
AU  - Laura Nunez Naveira
AU  - Nicolas Mercado
AU  - Kazuhiro Ito
TI  - AMPK signalling regulates Nrf2 localization and activity via sirtuins in a monocytic cell line
DP  - 2011 Sep 01
TA  - European Respiratory Journal
PG  - p424
VI  - 38
IP  - Suppl 55
4099  - http://erj.ersjournals.com/content/38/Suppl_55/p424.short
4100  - http://erj.ersjournals.com/content/38/Suppl_55/p424.full
SO  - Eur Respir J2011 Sep 01; 38
AB  - Nrf2 participate in the defence against oxidative stress by inducing anti-oxidant genes such as HO-1 and NQO1, which system is downregulated in COPD. AMPK and sirtuins are ageing related signals reported to control the expression of genes. Sirt1 is also down-regulated in COPD lung.Aims: To evaluate the effect of sirtuin inhibition and AMPK activation/inhibition on the nuclear localization and activity of Nrf2, and the expression of HO1 and NQO1.Methods: THP-1 monocytic cells were treated with a sirtuin inhibitor (sirtinol), hydrogen peroxide (H202) as oxidative stress reagent and AICAR and dorsomorphin as AMPK activator and inhibitor respectively. Nrf2 protein levels were measured by western blot and the samples were normalized against Lamin A/C. The mRNA levels of HO1 and NQO1 were measured by RT-PCR and normalized against GNB2L1. Nrf2 binding capacity was measured by ELISA.Results: H202 increased Nrf2 in the nucleus by 2-fold and pretreatment with sirtinol did not affect this induction. In contrast, although Nrf2 binding activity also increased by 50% with H202, preincubation with sirtinol abrogated this activation. Dorsomorphin treatment provoked a decrease in the nuclear levels of Nrf2 by 30%. In contrast, AICAR increased Nrf2 in the nucleus by 30% and augmented the mRNA levels of HO1 and NQO1 by 3.3 and 1.6-fold respectively.Discussion: Sirtuins depletion observed in COPD may cause a reduction of the anti-oxidative stress capacity by affecting Nrf2 regulation of HO1 and NQO1. AMPK may be participating in this oxidative stress defence. These results highlight the importance of the sirtuins/AMPK axis in COPD development and its possible use as targets for therapeutic purposes.