PMID- 22005302
OWN - NLM
STAT- MEDLINE
DCOM- 20120103
LR  - 20211203
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 121
IP  - 11
DP  - 2011 Nov
TI  - Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid 
      sensitivity in macrophages from COPD patients.
PG  - 4289-302
LID - 45144 [pii]
LID - 10.1172/JCI45144 [doi]
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.
FAU - Malhotra, Deepti
AU  - Malhotra D
AD  - Department of Environmental Health Sciences, Bloomberg School of Public Health, 
      Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Thimmulappa, Rajesh K
AU  - Thimmulappa RK
FAU - Mercado, Nicolas
AU  - Mercado N
FAU - Ito, Kazuhiro
AU  - Ito K
FAU - Kombairaju, Ponvijay
AU  - Kombairaju P
FAU - Kumar, Sarvesh
AU  - Kumar S
FAU - Ma, Jinfang
AU  - Ma J
FAU - Feller-Kopman, David
AU  - Feller-Kopman D
FAU - Wise, Robert
AU  - Wise R
FAU - Barnes, Peter
AU  - Barnes P
FAU - Biswal, Shyam
AU  - Biswal S
LA  - eng
GR  - U01 HL105569/HL/NHLBI NIH HHS/United States
GR  - P50ES015903/ES/NIEHS NIH HHS/United States
GR  - P50HL107169/HL/NHLBI NIH HHS/United States
GR  - P01 ES018176/ES/NIEHS NIH HHS/United States
GR  - R01 HL081205/HL/NHLBI NIH HHS/United States
GR  - P50 HL084945/HL/NHLBI NIH HHS/United States
GR  - P50 CA058184/CA/NCI NIH HHS/United States
GR  - U01HL105569/HL/NHLBI NIH HHS/United States
GR  - P50HL084945/HL/NHLBI NIH HHS/United States
GR  - P50 HL107169/HL/NHLBI NIH HHS/United States
GR  - P30 ES003819/ES/NIEHS NIH HHS/United States
GR  - P50 ES015903/ES/NIEHS NIH HHS/United States
GR  - P01ES018176/ES/NIEHS NIH HHS/United States
GR  - ES03819/ES/NIEHS NIH HHS/United States
GR  - HL081205/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Retracted Publication
DEP - 20111017
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Adrenal Cortex Hormones)
RN  - 0 (Isothiocyanates)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Nitrogen Oxides)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Sulfoxides)
RN  - 0 (Thiocyanates)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 3.5.1.98 (HDAC2 protein, human)
RN  - EC 3.5.1.98 (Hdac2 protein, mouse)
RN  - EC 3.5.1.98 (Histone Deacetylase 2)
RN  - GA49J4310U (sulforaphane)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
RIN - J Clin Invest. 2014 Dec;124(12):5521. PMID: 25438060
CIN - Fed Regist. 2019 Nov 14;84(220):61916-61917. PMID: 31749507
MH  - Adrenal Cortex Hormones/*pharmacology
MH  - Aged
MH  - Animals
MH  - Cell Line
MH  - Dexamethasone/pharmacology
MH  - Drug Resistance/drug effects
MH  - Glutathione/pharmacology
MH  - Histone Deacetylase 2/chemistry/*metabolism
MH  - Humans
MH  - In Vitro Techniques
MH  - Isothiocyanates
MH  - Lung/metabolism
MH  - Macrophages, Alveolar/*drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/deficiency/genetics/*metabolism
MH  - Nitrogen Oxides/chemistry
MH  - Pulmonary Disease, Chronic Obstructive/*drug therapy/*metabolism
MH  - Receptors, Glucocorticoid/metabolism
MH  - Sulfoxides
MH  - Thiocyanates/pharmacology
PMC - PMC3204828
EDAT- 2011/10/19 06:00
MHDA- 2012/01/04 06:00
PMCR- 2011/10/17
CRDT- 2011/10/19 06:00
PHST- 2010/09/16 00:00 [received]
PHST- 2011/09/14 00:00 [accepted]
PHST- 2011/10/19 06:00 [entrez]
PHST- 2011/10/19 06:00 [pubmed]
PHST- 2012/01/04 06:00 [medline]
PHST- 2011/10/17 00:00 [pmc-release]
AID - 45144 [pii]
AID - 10.1172/JCI45144 [doi]
PST - ppublish
SO  - J Clin Invest. 2011 Nov;121(11):4289-302. doi: 10.1172/JCI45144. Epub 2011 Oct 
      17.