Inhibition of HDACs (Histone Deacetylases) Ameliorates High-Fat Diet–Induced Hypertension Through Restoration of the MsrA (Methionine Sulfoxide Reductase A)/Hydrogen Sulfide Axis
| Autor: | Ga-Eun Yoon, Kwon Moo Park, Jee In Kim, GiBong Jang, Jin Ki Jung, Inkyeom Kim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Hydrogen sulfide Myocytes Smooth Muscle Naphthalenes Diet High-Fat Hydroxamic Acids Muscle Smooth Vascular Histones Mice chemistry.chemical_compound Internal Medicine medicine Animals Hydrogen Sulfide Promoter Regions Genetic Methionine sulfoxide reductase A biology Chemistry High fat diet Histone Deacetylase Inhibitors Mice Inbred C57BL Oxidative Stress Histone Biochemistry Vasoconstriction Methionine Sulfoxide Reductases Hypertension biology.protein Methionine sulfoxide reductase medicine.symptom MSRA |
| Zdroj: | Hypertension. 78:1103-1115 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.121.17149 |
| Popis: | Hydrogen sulfide (H 2 S) 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 H 2 S 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, H 2 S 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 H 2 S 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 H 2 S 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 H 2 S 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 H 2 S levels. MsrA expression is epigenetically regulated by HDAC inhibitors, providing HDAC inhibitors as a therapeutic option and MsrA and H 2 S as novel therapeutic targets. Graphic Abstract: An online graphic abstract is available for this article. |
| Databáze: | OpenAIRE |
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