Abstract
Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, participates in regulating cellular apoptosis, senescence and metabolism by deacetylating histones and multiple transcription factors. In this study, we aimed to determine the effect of SIRT1 on the apoptosis of vascular adventitial fibroblasts (VAFs) and related signaling pathways. SIRT1 was found in the nucleus of VAFs and translocated into the cytoplasm in response to tumor necrosis factor-α (TNF-α). Moreover, SIRT1 protein expression was reduced in VAFs stimulated with TNF-α. In addition, TNF-α increased the apoptosis of VAFs. Activation of SIRT1 by resveratrol (RSV) or overexpression of SIRT1 attenuated TNF-α-induced VAF apoptosis by decreasing the percentage of apoptotic cells and cleaved caspase-3 protein expression and increasing the Bcl-2/Bax ratio. In contrast, inhibition of SIRT1 by sirtinol/nicotinamide or knockdown of SIRT1 enhanced apoptosis of VAFs. On the other hand, knockdown of FoxO1 reduced TNF-α-induced VAF apoptosis. SIRT1 interacted with FoxO1 in VAFs by the co-immunoprecipitation assay. Further study showed that RSV or SIRT1 overexpression decreased acetylated-FoxO1 (Ac-FoxO1) protein expression in VAFs stimulated with TNF-α. Knockdown of SIRT1 resulted in an increase in Ac-FoxO1 protein expression. Taken together, these findings indicate that SIRT1 inhibits the apoptosis of VAFs, whereas FoxO1 promotes VAF apoptosis. Furthermore, the inhibitory effect of SIRT1 on VAF apoptosis is partly mediated by the deacetylation of FoxO1.
Similar content being viewed by others
References
Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800
Haigis MC, Guarente LP (2006) Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921
Zhang QJ, Wang Z, Chen HZ, Zhou S, Zheng W, Liu G, Wei YS, Cai H, Liu DP, Liang CC (2008) Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovasc Res 80:191–199
Clarke MCH, Figg N, Maguire JJ, Davenport AP, Goddard M, Littlewood TD, Bennett MR (2006) Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med 12:1075–1080
Sedding D, Koenig H, Krasteva G, Vogel S, Tilmanns H (2007) Sirt1 modulates foxo-dependent transcription and prevents smooth muscle cell apoptosis in response to oxidative stress. Circulation 116:S150–S155
Pillarisetti S (2008) A review of Sirt1 and Sirt1 modulators in cardiovascular and metabolic diseases. Recent Pat Cardiovasc Drug Discov 3:156–164
Yu W, Fu YC, Chen CJ, Wang X, Wang W (2009) SIRT1: a novel target to prevent atherosclerosis. J Cell Biochem 108:10–13
Sartore S, Chiavegato A, Faggin E, Franch R, Puato M, Ausoni S, Pauletto P (2001) Contribution of adventitial fibroblasts to neointima formation and vascular remodeling-From innocent bystander to active participant. Circ Res 89:1111–1121
Xu F, Ji J, Li L, Chen R, Hu WC (2007) Adventitial fibroblasts are activated in the early stages of atherosclerosis in the apolipoprotein E knockout mouse. Biochem Biophys Res Commun 352:681–688
Tanaka K, Nagata D, Hirata Y, Tabata Y, Sata RM (2011) Augmented angiogenesis in adventitia promotes growth of atherosclerotic plaque in apolipoprotein E-deficient mice. Atherosclerosis 215:366–373
Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, Wilcox JN (1996) Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 93:2178–2187
Malik N, Francis SE, Holt CM, Gunn J, Thomas GL, Shepherd L, Chamberlain J, Newman CMH, Cumberland DC, Crossman DC (1998) Apoptosis and cell proliferation after porcine coronary angioplasty. Circulation 98:1657–1665
Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappa B-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380
Vaziri H, Dessain SK, Eagon EN, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA (2001) hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159
Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, Sinclair DA (2004) Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13:627–638
Burgering BMT, Kops GJPL (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27:352–360
Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, Kollipara R, DePinho RA, Zeiher AM, Dimmeler S (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115:2382–2392
Park SH, Sakamoto H, Tsuji-Tamura K, Furuyama T, Ogawa M (2009) Foxo1 is essential for in vitro vascular formation from embryonic stem cells. Biochem Biophys Res Commun 390:861–866
Hosaka T, Biggs WH, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci USA 101:2975–2980
Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Nakayama K, Ikeda K, Motoyama N, Mori N (2004) Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279:34741–34749
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin YX, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015
Li GH, Chen YF, Kelpke SS, Oparil S, Thompson JA (2000) Estrogen attenuates integrin-beta(3)-dependent adventitial fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells. Circulation 101:2949–2955
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196
Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276:38837–38843
Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277:45099–45107
Ji QL, Yang LN, Zhou J, Lin R, Zhang JY, Lin QQ, Wang WR, Zhang KF (2012) Protective effects of paeoniflorin against cobalt chloride-induced apoptosis of endothelial cells via HIF-1 alpha pathway. Toxicol Vitro 26:455–461
Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere JL, Petit PX, Kroemer G (1995) Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 181:1661–1672
Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, Haendeler J, Mione M, Dejana E, Alt FW, Zeiher AM, Dimmeler S (2007) SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 21:2644–2658
Burlacu A (2003) Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med 7:249–257
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446
Tuleta I, Bauriedel G, Steinmetz M, Pabst S, Peuster M, Welsch U, Nickenig G, Skowasch D (2010) Apoptosis-regulated survival of primarily extravascular cells in proliferative active poststent neointima. Cardiovasc Pathol 19:353–360
Ling SH, Zhou LM, Li H, Dai AZ, Liu JP, Komesaroff PA, Sudhir K (2006) Effects of 17 beta-estradiol on growth and apoptosis in human vascular endothelial cells: influence of mechanical strain and tumor necrosis factor-alpha. Steroids 71:799–808
Zhang M, Yuan F, Liu H, Chen H, Qiu XB, Fang WY (2008) Inhibition of proliferation and apoptosis of vascular smooth muscle cells by ghrelin. Acta Biochim Biophys Sin 40:769–776
Ramana KV, Bhatnagar A, Srivastava SK (2004) Aldose reductase regulates TNF-alpha-induced cell signaling and apoptosis in vascular endothelial cells. FEBS Lett 570:189–194
Lalier L, Cartron PF, Juin P, Nedelkina S, Manon S, Bechinger B, Vallette FM (2007) Bax activation and mitochondrial insertion during apoptosis. Apoptosis 12:887–896
Lee HC, Yin PH, Lu CY, Chi CW, Wei YH (2000) Increase of mitochondria and mitochondrial DNA in response to oxidative stress in human cells. Biochem J 348:425–432
Obara H, Takayanagi A, Hirahashi J, Tanaka K, Wakabayashi G, Matsumoto K, Shimazu M, Shimizu N, Kitajima M (2000) Overexpression of truncated I kappa B alpha induces TNF-alpha-dependent apoptosis in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20:2198–2204
Xu JW, Ikeda K, Yamori Y (2007) Inhibitory effect of polyphenol cyanidin on TNF-alpha-induced apoptosis through multiple signaling pathways in endothelial cells. Atherosclerosis 193:299–308
Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21:2383–2396
Jin QH, Yan TT, Ge XJ, Sun C, Shi XG, Zhai QW (2007) Cytoplasm-localized SIRT1 enhances apoptosis. J Cell Physiol 213:88–97
Hou JL, Wang SH, Shang YC, Chong ZZ, Maiese K (2011) Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr Neurovasc Res 8:220–235
Dvir-Ginzberg M, Gagarina V, Lee EJ, Booth R, Gabay O, Hall DJ (2011) Tumor necrosis factor alpha-mediated cleavage and inactivation of sirT1 in human osteoarthritic chondrocytes. Arthritis Rheum 63:2363–2373
Li L, Zhang HN, Chen HZ, Gao P, Zhu LH, Li HL, Lv X, Zhang QJ, Zhang R, Wang Z, She ZG, Zhang R, Wei YS, Du GH, Liu DP, Liang CC (2011) SIRT1 acts as a modulator of neointima formation following vascular injury in mice. Circ Res 108:1180–1189
Zhang HN, Li L, Gao P, Chen HZ, Zhang R, Wei YS, Liu DP, Liang CC (2010) Involvement of the p65/RelA subunit of NF-kappa B in TNF-alpha-induced SIRT1 expression in vascular smooth muscle cells. Biochem Biophys Res Commun 397:569–575
Ou HC, Chou FP, Sheen HM, Lin TM, Yang CH, Sheu WHH (2006) Resveratrol, a polyphenolic compound in red wine, protects against oxidized LDL-induced cytotoxicity in endothelial cells. Clin Chim Acta 364:196–204
Li BY, Li XL, Cai Q, Gao HQ, Cheng M, Zhang JH, Wang JF, Yu F, Zhou RH (2011) Induction of lactadherin mediates the apoptosis of endothelial cells in response to advanced glycation end products and protective effects of grape seed procyanidin B2 and resveratrol. Apoptosis 16:732–745
Fu Z, Tindall DJ (2008) FOXOs, cancer and regulation of apoptosis. Oncogene 27:2312–2319
Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622
Urbich C, Knau A, Fichtlscherer S, Walter DH, Bruhl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S (2005) FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 19:974–976
Alikhani M, Alikhani ZB, Graves DT (2005) FOXO1 functions as a master switch that regulates gene expression necessary for tumor necrosis factor-induced fibroblast apoptosis. J Biol Chem 280:12096–12102
Kayal RA, Siqueira M, Alblowi J, McLean J, Krothapalli N, Faibish D, Einhorn TA, Gerstenfeld LC, Graves DT (2010) TNF-alpha mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis through FOXO1. J Bone Miner Res 25:1604–1615
Alikhani M, Roy S, Graves DT (2010) FOXO1 plays an essential role in apoptosis of retinal pericytes. Mol Vis 16:408–415
Li SY, Bian HT, Liu Z, Wang Y, Dai JH, He WF, Liao XG, Liu RR, Luo J (2012) Chlorogenic acid protects MSCs against oxidative stress by altering FOXO family genes and activating intrinsic pathway. Eur J Pharmacol 674:65–72
Huang HJ, Tindall DJ (2007) Dynamic FoxO transcription factors. J Cell Sci 120:2479–2487
Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, Gu W, Accili D (2008) SirT1 Gain of Function Increases Energy Efficiency and Prevents Diabetes in Mice. Cell Metab 8:333–341
Zhao T, Li JA, Chen AF (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299:E110–E116
Chae HD, Broxmeyer HE (2011) SIRT1 deficiency downregulates PTEN/JNK/FOXO1 pathway to block reactive oxygen species-induced apoptosis in mouse embryonic stem cells. Stem Cells Dev 20:1277–1285
Acknowledgments
This study was supported by the National Natural Science Foundation of China (No. 81072643 and No. 81270347), Natural Science Foundation of Shaanxi Province (2012JQ4025), and Fundamental Research Funds for the Central Universities (XJ08142011 and XJ08143045). We thank Prof. Jeng-Jiann Chiu (National Health Research Institutes, Taiwan) for his help in language.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, W., Yan, C., Zhang, J. et al. SIRT1 inhibits TNF-α-induced apoptosis of vascular adventitial fibroblasts partly through the deacetylation of FoxO1. Apoptosis 18, 689–701 (2013). https://doi.org/10.1007/s10495-013-0833-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-013-0833-7