SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease.
BACKGROUND
Abnormal inflammation and accelerated decline in lung function occur in patients with chronic obstructive pulmonary disease (COPD). Human sirtuin (SIRT1), an antiaging and antiinflammatory protein, is a metabolic NAD(+)-dependent protein/histone deacetylase that regulates proinflammatory mediators by deacetylating histone and nonhistone proteins.


OBJECTIVE
To determine the expression of SIRT1 in lungs of smokers and patients with COPD, and to elucidate the regulation of SIRT1 in response to cigarette smoke in macrophages, and its impact on nuclear factor (NF)-kappaB regulation.


METHODS
SIRT1 and NF-kappaB levels were assessed in lung samples of nonsmokers, smokers, and patients with COPD. Human monocyte-macrophage cells (MonoMac6) were treated with cigarette smoke extract (CSE) to determine the mechanism of CSE-mediated regulation of SIRT1 and its involvement in RelA/p65 regulation and IL-8 release.


RESULTS
Peripheral lungs of smokers and patients with COPD showed decreased levels of nuclear SIRT1, as compared with nonsmokers, associated with its post-translational modifications (formation of nitrotyrosine and aldehyde carbonyl adducts). Treatment of MonoMac6 cells with CSE showed decreased levels of SIRT1 associated with increased acetylation of RelA/p65 NF-kappaB. Mutation or knockdown of SIRT1 resulted in increased acetylation of nuclear RelA/p65 and IL-8 release, whereas overexpression of SIRT1 decreased IL-8 release in response to CSE treatment in MonoMac6 cells.


CONCLUSIONS
SIRT1 levels were reduced in macrophages and lungs of smokers and patients with COPD due to its post-translational modifications by cigarette smoke-derived reactive components, leading to increased acetylation of RelA/p65. Thus, SIRT1 plays a pivotal role in regulation of NF-kappaB-dependent proinflammatory mediators in lungs of smokers and patients with COPD.
Rajendrasozhan
Saravanan
S
Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Yang
Se-Ran
SR
Kinnula
Vuokko L
VL
Rahman
Irfan
I
D000107:Acetylation / Q000187:drug effects*; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects / Q000032:analysis; D012907:Smoking / Q000009:adverse effects* / Q000503:physiopathology; D014026:Nicotiana / Q000009:adverse effects / Q000737:chemistry
D012906:Smoke; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins