Abstract
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.
Highlights
DNA demethylation is an important process that maintains transcriptional activity of genes (Avrahami et al, 2015; Bigot et al, 2015; Wagner, Fernandez-Rebollo & Frobel, 2016; Zinovkina & Zinovkin, 2015)
We investigated whether compound H increases Klotho levels and attenuates aging-associated arterial stiffening and hypertension
Our results demonstrated that aging-related arterial stiffening and hypertension are attributed, at least in part, to the increased DNA methylation
Summary
DNA demethylation is an important process that maintains transcriptional activity of genes (Avrahami et al, 2015; Bigot et al, 2015; Wagner, Fernandez-Rebollo & Frobel, 2016; Zinovkina & Zinovkin, 2015). An increase in methylation in the promoter region of a gene diminishes the promoter activity and gene transcription (Wagner et al, 2016; Zinovkina & Zinovkin, 2015). Numerous studies showed that DNA methylation is increased with age (Alvares, Mayberry, Joyner, Lakowski & Ahmed, 2014; Avrahami et al, 2015; Bigot et al, 2015; Wagner et al, 2016; Zinovkina & Zinovkin, 2015). The prevalence of arterial stiffness and hypertension increases with age (Sun, 2015). Arterial stiffening is an independent predictor of cardiovascular outcomes, such as hypertension, myocardial infarction, cognitive decline in aging, stroke, and kidney diseases (Hashimoto & Ito, 2011, 2013; Karras et al, 2012; Kitzman et al, 2013; Sun, 2015).
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