title: Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients.
abstract: 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.
authors: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Deepti
authors: D
authors: Malhotra
authors: Rajesh K
authors: RK
authors: Thimmulappa
authors: Nicolas
authors: N
authors: Mercado
authors: Kazuhiro
authors: K
authors: Ito
authors: Ponvijay
authors: P
authors: Kombairaju
authors: Sarvesh
authors: S
authors: Kumar
authors: Jinfang
authors: J
authors: Ma
authors: David
authors: D
authors: Feller-Kopman
authors: Robert
authors: R
authors: Wise
authors: Peter
authors: P
authors: Barnes
authors: Shyam
authors: S
authors: Biswal
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000368:Aged; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D005978:Glutathione / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D017879:Isothiocyanates; D008168:Lung / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000737:chemistry; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology
chemical_list: D000305:Adrenal Cortex Hormones; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D009589:Nitrogen Oxides; D011965:Receptors, Glucocorticoid; D013454:Sulfoxides; D013861:Thiocyanates; D003907:Dexamethasone; C533423:HDAC2 protein, human; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; C016766:sulforaphane; D005978:Glutathione