SIRT1, an Antiinflammatory and Antiaging Protein, Is Decreased in Lungs of Patients with Chronic Obstructive Pulmonary Disease

Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2008; 177(8):861-70. DOI: 10.1164/rccm.200708-1269OC
Source: PubMed


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.
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.
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.
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.
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.

Download full-text


Available from: Saravanan Rajendrasozhan, Oct 01, 2015
1 Follower
19 Reads
  • Source
    • "Because FOXO transcription factors transactivate a series of target genes that have critical roles in the cellular response to stress stimuli, endogenous sirtuin1 may potentiate FOXO’s ability to detoxify ROS and to repair damaged DNA [35]. It has been reported that sirtuin1 levels were reduced in macrophages and lungs of smokers and patients with chronic obstructive pulmonary disease due to its post-translational modifications by cigarette smoke-derived reactive components [36]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, remains a major health problem. BPD is characterized by impaired alveolar development and complicated by pulmonary hypertension (PHT). Currently there is no specific treatment for BPD. Hydrogen sulfide (H2S), carbon monoxide and nitric oxide (NO), belong to a class of endogenously synthesized gaseous molecules referred to as gasotransmitters. While inhaled NO is already used for the treatment of neonatal PHT and currently tested for the prevention of BPD, H2S has until recently been regarded exclusively as a toxic gas. Recent evidence suggests that endogenous H2S exerts beneficial biological effects, including cytoprotection and vasodilatation. We hypothesized that H2S preserves normal alveolar development and prevents PHT in experimental BPD. We took advantage of a recently described slow-releasing H2S donor, GYY4137 (morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate) to study its lung protective potential in vitro and in vivo. In vitro, GYY4137 promoted capillary-like network formation, viability and reduced reactive oxygen species in hyperoxia-exposed human pulmonary artery endothelial cells. GYY4137 also protected mitochondrial function in alveolar epithelial cells. In vivo, GYY4137 preserved and restored normal alveolar growth in rat pups exposed from birth for 2 weeks to hyperoxia. GYY4137 also attenuated PHT as determined by improved pulmonary arterial acceleration time on echo-Doppler, pulmonary artery remodeling and right ventricular hypertrophy. GYY4137 also prevented pulmonary artery smooth muscle cell proliferation. H2S protects from impaired alveolar growth and PHT in experimental O2-induced lung injury. H2S warrants further investigation as a new therapeutic target for alveolar damage and PHT.
    PLoS ONE 03/2014; 9(3):e90965. DOI:10.1371/journal.pone.0090965 · 3.23 Impact Factor
  • Source
    • "It is widely expressed in numerous cell types, including ovarian cells. In non-ovarian cells, SIRT1 regulates metabolism, hormone secretion, cell cycle, cell differentiation , and it is protective against cellular oxidative stress, DNA damage, apoptosis, ageing and inflammation (Chen et al., 2005; Bordone et al., 2006; Fu et al., 2006; Haigis and Guarente, 2006; Wolf, 2006; Rajendrasozhan et al., 2008; Rodgers et al., 2008). Involvement of SIRT1 in the control of the cell cycle and apoptosis are well documented. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of either mTOR system/enzyme sirtuin1 (SIRT1) or transcription factor NF-κB in the direct control of ovarian function has not been estabished. The aim of our in vitro experiments was to examine the involvement of SIRT1 and the p65 and p50 subunits of NFκB in control of porcine ovarian granulosa cell functions and the interrelationships between SIRT1, NFκB (p65, p50) 30 and FSH in the ovary. Monolayers of primary granulosa cells were transfected with gene constructs encoding either SIRT1 or p65 and p50, and thereafter cultured with, or without, addition of FSH. The accumulation of markers of proliferation (cyclin B1 and cyclin-dependent protein kinase Cdc2/p34) and proteins p50, p65 and SIRT1 in the cells was detected by using SDS-PAGE/Western immunoblotting and immunocytochemistry. The secretion of progesterone (P4) and insulin-like growth factor I (IGF-I) was measured by using radioimmunoassay. It was observed that transfection of cells with a SIRT1 gene construct promoted accumulation of proliferation markers, Cdc2/p34, cyclin B1, decreased accumulation of p50 and p65 and stimulated release of P4 and IGF-I. Co-transfection of cells with cDNA p50 and cDNA p65 enhanced the accumulation of SIRT1 and the release of P4 but did not influence the release of IGF-I. Adding FSH to the culture medium stimulated accumulation of both subunits of NF-κB, as well as accumulation of Cdc2/p34, cyclin B1 and release of both P4 and IGF-I. The ability of FSH to promote NF-κB accumulation, the similarity of the main effects of FSH, SIRT1 and NF-κB, as well as the inability of NF-κB to substantially modify the the majority of FSH effects suggest that SIRT1/NF-κB system could be a mediator of FSH action on ovarian cell functions. On the other hand, SIRT1 was able to inhibit NF-κB and to change stimulatory the effect of FSH on NF-κB from stimulatory to inhibitory. This could suggest the existence of negative feedback control of FSH/NF-κB system by high amounts of SIRT1. Our observations (1) confirm the previous data on proliferation, P4 and IGF-I release in ovarian cells and their up-regulation by FSH, (2) demonstrate the presence of SIRT1, NF-κB/p50 and NF-κB/p65 in these cells, (3) show for the first time the involvement of SIRT1 and NF-κB in direct control of proliferation and secretory activity of ovarian cells, (4) represent the first data on interrelationships between FSH, SIRT1 and NF-κB within the ovary.
    Animal reproduction science 07/2013; 140(3-4). DOI:10.1016/j.anireprosci.2013.06.013 · 1.51 Impact Factor
  • Source
    • "Sirtinol (an inhibitor of SIRT1) augmented, whereas SRT1720 (a specific and potent SIRT1 activator ) inhibited, cigarette smoke-mediated proinflammatory cytokine release [13,29]. Furthermore, SIRT1 interacts with the RelA/ p65 subunit of NF-κB, and this interaction is disrupted by cigarette smoke, leading to increased acetylation of RelA/p65 in MonoMac6 cells [29]. A recent study has demonstrated the functional regulation of SIRT1 through NF-κB-dependent STAT3 expression in mitochondria [101]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuin1 (SIRT1) regulates inflammation, aging (lifespan and healthspan), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. SIRT1 level and activity are decreased in chronic inflammatory conditions and aging where oxidative stress occurs. SIRT1 is regulated by a NAD(+)-dependent DNA repair enzyme poly(ADP-ribose)-polymerase-1 (PARP-1), and subsequent NAD(+) depletion by oxidative stresses may have consequent effects on inflammatory and stress responses as well as cellular senescence. SIRT1 has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to post-translational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of SIRT1 leads to the loss of its control on acetylation of target proteins including p53, RelA/p65 and FOXO3, thereby enhancing the inflammatory, pro-senescent and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox post-translational modifications of SIRT1 and its role in PARP1, NF-κB activation, FOXO3 and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging are discussed. Furthermore, we also discussed various novel ways to activate SIRT1 either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases.
    Free Radical Biology and Medicine 03/2013; 61. DOI:10.1016/j.freeradbiomed.2013.03.015 · 5.74 Impact Factor
Show more