Activation of DNA demethylases attenuates aging-associated arterial stiffening and hypertension

Research output: Contribution to journalArticle

Abstract

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.

LanguageEnglish (US)
Article numbere12762
JournalAging Cell
Volume17
Issue number4
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

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Vascular Stiffness
Hypertension
DNA
Pulse Wave Analysis
DNA Methylation
Aorta
Down-Regulation
Rejuvenation
Kidney
AMP-Activated Protein Kinases
Elastin
Serum
Matrix Metalloproteinases
Smooth Muscle Myocytes
Arterial Pressure
Collagen
Arteries
Blood Pressure
Therapeutics

All Science Journal Classification (ASJC) codes

  • Aging
  • Cell Biology

Cite this

Activation of DNA demethylases attenuates aging-associated arterial stiffening and hypertension. / Chen, Kai; Sun, Zhongjie.

In: Aging Cell, Vol. 17, No. 4, e12762, 01.08.2018.

Research output: Contribution to journalArticle

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