Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2.
Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2.
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组蛋白脱乙酰酶 3 抑制通过 Nrf2 缓解 2 型糖尿病诱导的内皮功能障碍
DOI：
10.1186/s12964-020-00681-z
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发表时间：
2021-03-18
期刊：
影响因子：
--
通讯作者：
Cong W
中科院分区：
文献类型：
--
作者：
Huang S;Chen G;Sun J;Chen Y;Wang N;Dong Y;Shen E;Hu Z;Gong W;Jin L;Cong W
BackgroundThe mechanism underlying endothelial dysfunction leading to cardiovascular disease in type 2 diabetes mellitus (T2DM) remains unclear. Here, we show that inhibition of histone deacetylase 3 (HDAC3) reduced inflammation and oxidative stress by regulating nuclear factor-E2-related factor 2 (Nrf2), which mediates the expression of anti-inflammatory- and pro-survival-related genes in the vascular endothelium, thereby improving endothelial function.MethodsNrf2 knockout (Nrf2 KO) C57BL/6 background mice, diabetic db/db mice, and control db/m mice were used to investigate the relationship between HDAC3 and Nrf2 in the endothelium in vivo. Human umbilical vein endothelial cells (HUVECs) cultured under high glucose-palmitic acid (HG-PA) conditions were used to explore the role of Kelch-like ECH-associated protein 1 (Keap1) –Nrf2–NAPDH oxidase 4 (Nox4) redox signaling in the vascular endothelium in vitro. Activity assays, immunofluorescence, western blotting, qRT-PCR, and immunoprecipitation assays were used to examine the effect of HDAC3 inhibition on inflammation, reactive oxygen species (ROS) production, and endothelial impairment, as well as the activity of Nrf2-related molecules.ResultsHDAC3 activity, but not its expression, was increased in db/db mice. This resulted in de-endothelialization and increased oxidative stress and pro-inflammatory marker expression in cells treated with the HDAC3 inhibitor RGFP966, which activated Nrf2 signaling. HDAC3 silencing decreased ROS production, inflammation, and damage-associated tube formation in HG-PA-treated HUVECs. The underlying mechanism involved the Keap1–Nrf2–Nox4 signaling pathway.ConclusionThe results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM.Video Abstract
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
5.5
作者：
Basuroy, Shyamali;Bhattacharya, Sujoy;Parfenova, Helena
通讯作者：
Parfenova, Helena
影响因子：
10.8
作者：
Brill, A;Elinav, H;Varon, D
通讯作者：
Varon, D
DOI：
10.1161/01.atv.0000247247.89787.e7
发表时间：
2006-12-01
影响因子：
8.7
作者：
Inoue, Kenji;Kobayashi, Mika;Minami, Takashi
通讯作者：
Minami, Takashi
影响因子：
5.1
作者：
Cho, N. H.;Shaw, J. E.;Malanda, B.
通讯作者：
Malanda, B.