Redox regulation of SIRT1 in inflammation and cellular senescence

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.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…Further studies will be needed to unveil the molecular mechanisms of sirtuins in the remodeling of chromatin via epigenetic modification of histone and nonhistone proteins [reviewed in Ref. (Hwang, Yao, Caito, Sundar & Rahman, 2013; Xie, Zhang & Zhang, 2013)]. In conclusion, enhancement of metabolic flexibility coupled with efficient redox control and energy homeostasis underlies the positive influence of CYB5R3 and NQO1 co‐expression on health and longevity.…”

Sirtuin-1 (SIRT1) Is Required for Promoting Chondrogenic Differentiation of Mesenchymal Stem Cells

“…SIRT1 is able to de-acetylate many different transcription factors in the nucleus such as p53, NF-B, myogenic differentiation, high mobility group I, E2F transcription factor, and forkhead box O, thus playing an essential role in cell differentiation, cell survival, tumorigenesis, inflammation, and metabolism (27)(28)(29)(30)(31). Moreover, SIRT1 targets chromatin (histones) as well as nonchromatin proteins in the cells, has been linked to transcriptional silencing, and appears to play a key role in inflammation (32,33). More recently, several reports have shown that normal cartilage homeostasis requires enzymatically active SIRT1 protein in vivo (34 -36).…”

Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Cellular Senescence in Human Umbilical Vein Endothelial Cells

“…Sirtuin 1 (Sirt1), the closest homologue of silent information regulator2 (Sir2), has been identified to be a NAD ＋ -dependent deacetylase whose activity plays a significant role in the processes of senescence, apoptosis and cell cycle modulation by regulating the acetylation of lysine groups of many transcriptional factors and proteins, such as histones, p53 and FOXO transcriptional factors [17][18][19] . In addition, oxidative stress has been shown to reduce the cellular NAD ＋ content by suppressing the activation of intracellular nicotinamide phosphoribosyltransferase (iNampt), the rate-limiting enzyme for NAD ＋ biosynthesis derived from nicotinamide (NAM), and decreasing the Sirt1 activity 10,[20][21][22] . Therefore, Sirt1 is considered to be a key player in the promotion of oxidative stress-mediated cellular senescence 23) .…”

“…Since oxidative stress has been demonstrated to cause cellular senescence due to impairment of the iNampt-NAD ＋ -Sirt1 system 10,[20][21][22][23] , we examined the effects of apocynin (600 μmol/L) 44) , a specific NADPH oxidase inhibitor, on IS-induced cellular senescence in HUVECs. As shown in Fig.…”