Recurrent cigarette smoke exposure impairs SIRT1 shuttling in bronchial epithelial cells

Abstract

Introduction and background. The protein deacetylase SIRT1 is an anti-ageing molecule that is down-regulated in chronic obstructive pulmonary disease (COPD). SIRT1 maintains genomic stability and regulates antioxidant genes, and its function is known to be controlled by SIRT1 shuttling between nuclei and cytoplasmic fraction. Aims and objectives. We investigated the molecular dynamics of SIRT1 after exposure of airway epithelial cells to cigarette smoke extract (CSE). Methods and results. In primary bronchial epithelial cells (monolayer and air-liquid interface) and BEAS-2B cell line, SIRT1 was located predominantly in cytoplasmic fraction, but a single dose of CSE induced dynamic SIRT1 shuttling from cytoplasm to the nucleus, mainly through the activation of phosphatidylinositol 3-kinase-α (PI3Kα). Such SIRT1 nuclear shuttling strongly induced the antioxidant superoxide dismutase-2 (SOD2) mRNA, thus protecting against oxidative stress. However, when BEAS-2B cells were primed with the repeated CSE exposure, CSE-inducedSIRT1 shuttling and resultant SOD2 mRNA induction were significantly impaired, which was mimicked by treatment with a SIRT1 inhibitor sirtinol. Conclusions. Our results suggest that recurrent cigarette smoke exposure potentially impairs SIRT1 shuttling in bronchial epithelial cells, resulting in reduced protection against exogenous oxidative stress.