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Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension
DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052484/ https://www.ncbi.nlm.nih.gov/pubmed/29659128 http://dx.doi.org/10.1111/acel.12762 |
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author | Chen, Kai Sun, Zhongjie |
author_facet | Chen, Kai Sun, Zhongjie |
author_sort | Chen, Kai |
collection | PubMed |
description | DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice. |
format | Online Article Text |
id | pubmed-6052484 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-60524842018-08-01 Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension Chen, Kai Sun, Zhongjie Aging Cell Original Articles DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice. John Wiley and Sons Inc. 2018-04-16 2018-08 /pmc/articles/PMC6052484/ /pubmed/29659128 http://dx.doi.org/10.1111/acel.12762 Text en © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Chen, Kai Sun, Zhongjie Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title | Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title_full | Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title_fullStr | Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title_full_unstemmed | Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title_short | Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension |
title_sort | activation of dna demethylases attenuates aging‐associated arterial stiffening and hypertension |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052484/ https://www.ncbi.nlm.nih.gov/pubmed/29659128 http://dx.doi.org/10.1111/acel.12762 |
work_keys_str_mv | AT chenkai activationofdnademethylasesattenuatesagingassociatedarterialstiffeningandhypertension AT sunzhongjie activationofdnademethylasesattenuatesagingassociatedarterialstiffeningandhypertension |