Academic Journal
Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk
| العنوان: | Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk |
|---|---|
| المؤلفون: | Zannas, Anthony S., Jia, Meiwen, Hafner, Kathrin, Baumert, Jens, Wiechmann, Tobias, Pape, Julius C., Arloth, Janine, Ködel, Maik, Martinelli, Silvia, Roitman, Maria, Roeh, Simone, Haehle, Andreas, Emeny, Rebecca T., Iurato, Stella, Carrillo-Roa, Tania, Lahti, Jari, Räikkönen, Katri, Eriksson, Johan G., Drake, Amanda J., Waldenberger, Melanie, Wahl, Simone, Kunze, Sonja, Lucae, Susanne, Bradley, Bekh, Gieger, Christian, Hausch, Felix, Smith, Alicia K., Ressler, Kerry J., Mueller-Myhsok, Bertram, Ladwig, Karl-Heinz, Rein, Theo, Gassen, Nils C., Binder, Elisabeth B. |
| المساهمون: | Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Developmental Psychology Research Group |
| بيانات النشر: | National Academy of Sciences |
| سنة النشر: | 2019 |
| المجموعة: | Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: | aging, epigenetics, FKBP5, inflammation, psychosocial stress, ADVERSE CHILDHOOD EXPERIENCES, ALL-CAUSE MORTALITY, C-REACTIVE PROTEIN, DNA METHYLATION, DEPRESSIVE SYMPTOMS, LYMPHOCYTE RATIO, HEALTHY-MEN, DISEASE, HEART, IL-8, Psychology, General medicine, internal medicine and other clinical medicine |
| الوصف: | Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities. ; Peer reviewed |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | This work was supported by a Marie-Sklodowska Curie fellowship (H2020 Grant 653240) to A.S.Z., a grant from the National Institute of Mental Health (MH071538) to K.J.R., a European Research Council starting grant within the FP7 Framework to E.B.B. (Grant 281338, GxE molmech), a grant from the National Institute of Mental Health (U19 MH069056), a grant by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (Grant 01ZX1314J) to E.B.B., and by the Academy of Finland (Grants 284859, 2848591, and 312670). Part of this work has been included and presented in the PhD dissertation of A.S.Z. (63).; Zannas , A S , Jia , M , Hafner , K , Baumert , J , Wiechmann , T , Pape , J C , Arloth , J , Ködel , M , Martinelli , S , Roitman , M , Roeh , S , Haehle , A , Emeny , R T , Iurato , S , Carrillo-Roa , T , Lahti , J , Räikkönen , K , Eriksson , J G , Drake , A J , Waldenberger , M , Wahl , S , Kunze , S , Lucae , S , Bradley , B , Gieger , C , Hausch , F , Smith , A K , Ressler , K J , Mueller-Myhsok , B , Ladwig , K-H , Rein , T , Gassen , N C & Binder , E B 2019 , ' Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 116 , no. 23 , pp. 11370-11379 . https://doi.org/10.1073/pnas.1816847116; ORCID: /0000-0002-4310-5297/work/59924368; ORCID: /0000-0003-3124-3470/work/59926713; http://hdl.handle.net/10138/304027; c0b2619e-7717-4c94-abc2-6dcaa4e18635; 000470136000047 |
| الاتاحة: | http://hdl.handle.net/10138/304027 |
| Rights: | cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| رقم الانضمام: | edsbas.CF4CBF75 |
| قاعدة البيانات: | BASE |
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