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Inhibition of HDACs (Histone Deacetylases) Ameliorates High-Fat Diet-Induced Hypertension Through Restoration of the MsrA (Methionine Sulfoxide Reductase A)/Hydrogen Sulfide Axis

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Author(s)
Jin Ki JungGa-Eun YoonGiBong JangKwon Moo ParkInKyeom KimJee In Kim
Keimyung Author(s)
Kim, Jee In
Department
Dept. of Molecular Medicine (분자의학)
Journal Title
Hypertension
Issued Date
2021
Volume
78
Issue
4
Keyword
high fat diethistone deacetylaseshydrogen sulfidehypertensionmethionine sulfoxide reductasevasoconstriction
Abstract
Hydrogen sulfide (H2S) is an endogenous gaseous antioxidant and antihypertensive molecule produced during the homocysteine metabolism. MsrA (methionine sulfoxide reductase A) enables the metabolism of homocysteine by reducing methionine sulfoxide to methionine. Although HDAC (histone deacetylase) inhibition has been reported to show blood pressure lowering effects, their effects on endogenous H2S production are largely unknown. Here, we assessed the relevance of MsrA in high-fat diet (HFD)-induced hypertension and the effect of HDAC inhibition on MsrA expression, H2S production, and hypertension. Male C57BL/6 mice were fed a normal diet or HFD. HFD increased blood pressure and activities of HDAC3 and 6 but downregulated MsrA in the mesenteric arteries and the serum H2S level. HFD upregulated 4 hydroxynonenal, TNF (tumor necrosis factor)-α, and IL (interleukin)-6, and vasocontractile proteins. The histone H3 acetylation of the MsrA promoter was decreased by HFD. In hypertensive HFD-fed mice, administration of the HDAC inhibitor CG200745 lowered blood pressure and increased serum H2S level. CG200745 increased acetylation of histone H3 and MsrA levels in the mesenteric arteries while downregulating oxidative stress, inflammation, and vasocontractile proteins. Silencing of MsrA in the vascular smooth muscle cells recapitulated HFD-induced in vivo hypertensive effects. CG200745 increased the histone H3 acetylation of the MsrA promoter, MsrA expression, and H2S production in vascular smooth muscle cells, supporting the in vivo results. Collectively, HFD-induced downregulation of MsrA plays a pivotal role in HFD-induced hypertension by reducing H2S levels. MsrA expression is epigenetically regulated by HDAC inhibitors, providing HDAC inhibitors as a therapeutic option and MsrA and H2S as novel therapeutic targets.
Keimyung Author(s)(Kor)
김지인
Publisher
School of Medicine (의과대학)
Citation
Jin Ki Jung et al. (2021). Inhibition of HDACs (Histone Deacetylases) Ameliorates High-Fat Diet-Induced Hypertension Through Restoration of the MsrA (Methionine Sulfoxide Reductase A)/Hydrogen Sulfide Axis. Hypertension, 78(4), 1103–1115. doi: 10.1161/HYPERTENSIONAHA.121.17149
Type
Article
ISSN
1524-4563
Source
https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.17149
DOI
10.1161/HYPERTENSIONAHA.121.17149
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/43947
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Molecular Medicine (분자의학)
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