Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension
| Autor: | Kai Chen, Zhongjie Sun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
AMPK medicine.medical_specialty Aging hypertension Blood Pressure 030204 cardiovascular system & hematology Pulse Wave Analysis demethylase 03 medical and health sciences Mice 0302 clinical medicine Enos Internal medicine medicine Animals Klotho Pulse wave velocity secreted Klotho Cells Cultured Histone Demethylases Sirt1 biology Cell Biology Original Articles compound H Arteries medicine.disease biology.organism_classification DNA demethylase activity DNA Demethylation 030104 developmental biology Blood pressure Endocrinology arterial stiffness Arterial stiffness biology.protein Demethylase Original Article Elastin |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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