In this section
@article{Malhotra:2011,
author = {Malhotra, D and Thimmulappa, RK and Mercado, N and Ito, K and Kombairaju, P and Kumar, S and Ma, J and Feller-Kopman, D and Barnes, P and Biswal, S},
journal = {J Clin Invest},
pages = {4289--4302},
title = {Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients},
volume = {121},
year = {2011}
}
TY - JOUR
AB - Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids - normally highly effective antiinflammatory drugs - has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.
AU - Malhotra,D
AU - Thimmulappa,RK
AU - Mercado,N
AU - Ito,K
AU - Kombairaju,P
AU - Kumar,S
AU - Ma,J
AU - Feller-Kopman,D
AU - Barnes,P
AU - Biswal,S
EP - 4302
PY - 2011///
SP - 4289
TI - Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients
T2 - J Clin Invest
VL - 121
ER -
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