Sirtuins and chemokines as markers of replicative and induced senescence of human endotheliocytes
https://doi.org/10.29413/ABS.2022-7.5-2.2
Abstract
Background. One of the factors of the pathogenesis of atherosclerosis and other cardiovascular diseases is induced endothelial senescence. In this regard, the urgent task of molecular biology and medicine is the search for molecules that affect the process of vascular endotheliocytes senescence.
The aim. To assess the expression of Sirt-1,3,6 and chemokines IL-4, CXCL11 in the replicative and induced senescence of human endotheliocytes.
Materials and methods. The study was conducted on the primary culture of isolated human umbilical vein endothelial cells (HUVECs). HUVECs were cultured under conditions of replicative (natural) and lipopolysaccharide induced senescence.
Results. The synthesis of Sirt-1,3,6, IL-4 and CXCL11 was evaluated using western blot analysis. We revealed a decrease in Sirt-1,3,6 synthesis by 1.6–1.8 times (р < 0.05) in the conditions of HUVEC replicative senescence. Induced senescence of endotheliocytes is characterized by a more pronounced decrease (1.7–3.4 times; р < 0.05) in the Sirt-1,3,6 synthesis. CXCL11 synthesis increases by 1.4 times (р < 0.05) in replicative and by 3.4 times (р < 0.05) in induced HUVEC senescence. IL-4 synthesis increases by 4.7 times in conditions of induced HUVEC senescence and doesn’t have changes in replicative senescence of endotheliocytes.
Conclusion. These data obtained indicate that sirtuins and chemokines play an important role in the development of endothelial dysfunction observed in natural and induced senescence.
About the Authors
D. V. Savitskiy
Saint-Petersburg Institute of Bioregulation and Gerontology
Russian Federation
Russian Federation
Dmitriy V. Savitskiy – Research Officer at the Laboratory of Pathologic Physiology of Cardiovascular System
Dynamo ave. 3, Saint Petersburg 197110
N. S. Linkova
Saint-Petersburg Institute of Bioregulation and Gerontology; Academy of Postgraduate Education, Federal Research and Clinical Center of Specialized Medical Care and Medical
Technologies, FMBA of Russia; Belgorod State National Research University
Russian Federation
Russian Federation
Natalia S. Linkova – Dr. Sc. (Biol.), Docent, Head of the Laboratory of Molecular Mechanisms of Aging; Professor at the Department of Therapy, Geriatrics and Anti-Aging Medicine; Senior Research Officer at the Laboratory of Problems of Aging
Dynamo ave. 3, Saint Petersburg 197110
Volokolamskoye highway 91, Moscow 12537
Pobedy str. 85, Belgorod 308015
E. O. Kozhevnikova
Saint-Petersburg Institute of Bioregulation and Gerontology
Russian Federation
Russian Federation
Ekaterina O. Kozhevnikova – Cand. Sc. (Biol.), Research Officer at the Laboratory of Biogerontology
Dynamo ave. 3, Saint Petersburg 197110
K. L. Kozlov
Saint-Petersburg Institute of Bioregulation and Gerontology; Kirov Military Medical Academy
Russian Federation
Russian Federation
Kirill L. Kozlov – Dr. Sc. (Med.), Professor, Head of the Department of Clinical Gerontology and Geriatrics; Professor at the First Department and Clinic of Surgery (Advanced Medical Education)
Dynamo ave. 3, Saint Petersburg 197110
Akademika Lebedeva str. 6, Saint Petersburg 194044
E. M. Paltseva
Russian Academy of Sciences
Russian Federation
Russian Federation
Ekaterina M. Paltseva – Dr. Sc. (Med.), Docent, Research Officer
Leninskiy ave. 14, Moscow 119991
T. V. Kvetnaia
Saint-Petersburg Institute of Bioregulation and Gerontology
Russian Federation
Russian Federation
Tatiana V. Kvetnaia – Dr. Sc. (Biol.), Professor, Head of the Laboratory of Biogerontology
Dynamo ave. 3, Saint Petersburg 197110
References
1. Chen J, Goligorsky MS. Premature senescence of endothelial cells: Methusaleh’s dilemma. Am J Physiol Heart Circ Physiol. 2006; 290(5): H1729-H1739. doi: 10.1152/ajpheart.01103.2005
2. Gorenne I, Kavurma M, Scott S, Bennett M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res. 2006; 72(1): 9-17. doi: 10.1016/j.cardiores.2006.06.004
3. Erusalimsky JD. Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol (1985). 2009; 106(1): 326-332. doi: 10.1152/japplphysiol.91353.2008
4. Van Deursen JM. The role of senescent cells in ageing. Nature. 2014; 509(7501): 439-446. doi: 10.1038/nature13193
5. Denisova TP, Lipatova TE, Alipova LN, Yegorova AV. Interaction of atherosclerosis and ageing: Is there any discussion questionable? Saratov Journal of Medical Scientific Research. 2018; 14(2): 322-327. (In Russ.).
6. Tyrrell DJ, Goldstein DR. Ageing and atherosclerosis: Vascular intrinsic and extrinsic factors and potential role of IL-6. Nat Rev Cardiol. 2021; 18(1): 58-68. doi: 10.1038/s41569-020-0431-7
7. Vasko R, Xavier S, Chen J, Lin CH, Ratliff B, Rabadi M, et al. Endothelial sirtuin 1 deficiency perpetrates nephrosclerosis through downregulation of matrix metalloproteinase-14: Relevance to fibrosis of vascular senescence. J Am Soc Nephrol. 2014; 25(2): 276-291. doi: 10.1681/ASN.2013010069
8. Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, et al. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. 2010; 30(19): 4712-4721. doi: 10.1128/MCB.00657-10
9. Stein S, Lohmann C, Schafer N, Hofmann J, Rohrer L, Besler C, et al. SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur Heart J. 2010; 31(18): 2301-2309. doi: 10.1093/eurheartj/ehq107
10. Donato AJ, Magerko KA, Lawson BR, Durrant JR, Lesniewski LA, Seals DR. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans. J Physiol. 2011; 589(Pt 18_: 4545-4554. doi: 10.1113/jphysiol.2011.211219
11. Tao R, Xiong X, DePinho RA, Deng CX, Dong XC. FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression. J Biol Chem. 2013; 288(41): 29252-29259. doi: 10.1074/jbc.M113.481473
12. Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013; 63: 222-234. doi: 10.1016/j.freeradbiomed.2013.05.002
13. Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S, Bowers L, et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab. 2014; 20(5): 827-839. doi: 10.1016/j.cmet.2014.08.011
14. Lin CH, Chen J, Ziman B, Marshall S, Maizel J, Goligorsky MS. Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy? Am J Physiol Heart Circ Physiol. 2014; 306(12): H1692-H1699. doi: 10.1152/ajpheart.00064.2014
15. Balestrieri ML, Rizzo MR, Barbieri M, Paolisso P, D’Onofrio N, Giovane A, et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes. 2015; 64(4): 1395-1406. doi: 10.2337/db14-1149
16. Maksin-Matveev A, Kanfi Y, Hochhauser E, Isak A, Cohen HY, Shainberg A. Sirtuin 6 protects the heart from hypoxic damage. Exp Cell Res. 2015; 330(1): 81-90. doi: 10.1016/j.yexcr.2014.07.013
17. Oganov RG, Zakirova NE, Zakirova AN, Salakhova GM, Plotnikova MR. Immuno-inflamatory responses in acute coronary syndrome. Rational Pharmacotherapy in Cardiology. 2007; 5: 15-19. (In Russ.). doi: 10.20996/1819-6446-2007-3-5-6-8
18. Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, et al. Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest. 1999; 104(8): 1041-1050. doi: 10.1172/JCI6993
19. Szodoray P, Timar O, Veres K, Der H, Szomjak E, Lakos G, et al. Th1/Th2 imbalance, measured by circulating and intra cytoplasmic inflammatory cytokines-immunological alterations in acute coronary syndrome and stable coronary artery disease. Scand J Immunol. 2006; 64(3): 336-344. doi: 10.1111/j.1365-3083.2006.01816.x
20. Lee YW, Lee WH, Kim PH. Oxidative mechanisms of IL-4-induced IL-6 expression in vascular endothelium. Cytokine. 2010; 49(1): 73-79. doi: 10.1016/j.cyto.2009.08.009
21. Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM. Left ventricular dysfunction and CXCR3 ligands in hypertension: From animal experiments to a population-based pilot study. PloS One. 2015; 10(10): e0141394. doi: 10.1371/journal.pone.0141394
22. Chalubinski M, Wojdan K, Luczak E, Gorzelak P, Borowiec M, Gajewski A, et al. IL-33 and IL-4 impair barrier functions of human vascular endothelium via different mechanisms. Vascul Pharmacol. 2015; 73; 57-63. doi: 10.1016/j.vph.2015.07.012
23. Khokhlov AN, Klebanov AA, Karmushakov AF, Shilovsky GA, Nasonov MM, Morgunova GV. Testing of anti-aging drugs in experiments on cell cultures: Choosing the correct model system. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2014; 1: 13-18. (In Russ.).
24. Yi S, Lin K, Jiang T, Shao W, Huang C, Jiang B, et al. NMRbased metabonomic analysis of HUVEC cells during replicative senescence. Aging. 2020; 12(4): 3626-3646. doi: 10.18632/aging.102834
25. Schumann RR, Belka C, Reuter D, Lamping N, Kirschning CJ, Weber JR, et al. Lipopolysaccharide activates caspase-1 (interleukin-1-converting enzyme) in cultured monocytic and endothelial cells. Blood. 1998; 91: 577.
26. Messmer UK, Briner VA, Pfeilschifter J. Tumor necrosis factor-α and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells. Kidney Int. 1999; 55(6): 2322. doi: 10.1046/j.1523-1755.1999.00473.x
27. Pan X, Wu B, Fan X, Xu G, Ou C, Chen M. YAP accelerates vascular senescence via blocking autophagic flux and activating mTOR. J Cell Mol Med. 2021; 25(1): 170-183. doi: 10.1111/jcmm.15902
28. Yamashita S, Ogawa K, Ikei T, Udono M, Fujiki T, Katakura Y. SIRT1 prevents replicative senescence of normal human umbilical cord fibroblast through potentiating the transcription of human telomerase reverse transcriptase gene. Biochem Biophys Res Commun. 2012; 417(1): 630-634. doi: 10.1016/j.bbrc.2011.12.021
29. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell. 2008; 135(5): 907-918. doi: 10.1016/j.cell.2008.10.025
30. Michishita E, McCord RA, Berber E, Mostoslavsky R, Vann J, Park SK, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008; 452(7186): 492-496. doi: 10.1038/nature06736
31. Watroba M, Dudek I, Skoda M, Stangret A, Rzodkiewicz P, Szukiewicz D. Sirtuins, epigenetics and longevity. Ageing Res Rev. 2017; 40: 11-19. doi: 10.1016/j.arr.2017.08.001
32. Anwar T, Khosla S, Ramakrishna G. Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status. Cell Cycle. 2016; 15(14): 1883-1897. doi: 10.1080/15384101.2016.1189041
33. Son MJ, Kwon Y, Son T, Cho YS. Restoration of mitochondrial NAD(+) levels delays stem cell senescence and facilitates reprogramming of aged somatic cells. Stem Cells. 2016; 34(12): 2840-2851. doi: 10.1002/stem.2460
34. Chen J, Xie JJ, Jin MY, Gu YT, Wu CC, Guo WJ, et al. Sirt6 overexpression suppresses senescence and apoptosis of nucleus pulposus cells by inducing autophagy in a model of intervertebral disc degeneration. Cell Death Dis. 2018; 9(2): 56. doi: 10.1038/s41419-017-0085-5
35. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124(2): 315-329. doi: 10.1016/j.cell.2005.11.044
36. Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J Clin Invest. 2012; 122(6): 2032-2045. doi: 10.1172/JCI60132
37. Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010; 106(8): 1384-1393. doi: 10.1161/CIRCRESAHA.109.215483
38. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, et al. Human SIR2 deacetylates p53 and antagonizes PML/ p53-induced cellular senescence. EMBO J. 2002; 21(10): 2383-2396. doi: 10.1093/emboj/21.10.2383
39. Rimmele P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, et al. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem Cell Reports. 2014; 3(1): 44-59. doi: 10.1016/j.stemcr.2014.04.015
40. Chen J, Xavier S, Moskowitz-Kassai E, Chen R, Lu CY, Sanduski K, et al. Cathepsin cleavage of sirtuin 1 in endothelial progenitor cells mediates stress-induced premature senescence. Am J Pathol. 2012; 180(3): 973-983. doi: 10.1016/j.ajpath.2011.11.033
Review
For citations:
Savitskiy D.V., Linkova N.S., Kozhevnikova E.O., Kozlov K.L., Paltseva E.M., Kvetnaia T.V. Sirtuins and chemokines as markers of replicative and induced senescence of human endotheliocytes. Acta Biomedica Scientifica. 2022;7(5-2):12-20. (In Russ.) https://doi.org/10.29413/ABS.2022-7.5-2.2
Views:
706
Email this article 
