Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2

• Published in: Cell communication and signaling 2021-03, Vol.19 (1), p.35-35, Article 35
• Main Authors: Huang, Shuai, Chen, Gen, Sun, Jia, Chen, Yunjie, Wang, Nan, Dong, Yetong, Shen, Enzhao, Hu, Zhicheng, Gong, Wenjie, Jin, Litai, Cong, Weitao
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Biotechnology; Cardiovascular diseases; Cell adhesion & migration; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus - pathology; Endothelial cells; Endothelial dysfunction; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Glucose; HDAC3; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunofluorescence; Immunoprecipitation; Inflammation; Kelch-Like ECH-Associated Protein 1 - metabolism; Laboratories; Mice; Mice, Inbred C57BL; NAD(P)H oxidase; NADPH Oxidase 4 - antagonists & inhibitors; NADPH Oxidase 4 - metabolism; NF-E2-Related Factor 2 - metabolism; Nitric oxide; NOX4 protein; Nrf2; Oxidative stress; Palmitic acid; Protective Agents - pharmacology; Protein Binding - drug effects; Reactive oxygen species; Signal transduction; T2DM; Therapeutic targets; Transcription factors; Tumor necrosis factor-TNF; Umbilical vein; Western blotting
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-020-00681-z

The 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. Nrf2 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. HDAC3 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. The results of this study suggest the potential of HDAC3 as a therapeutic target for the treatment of endothelial dysfunction in T2DM. Video Abstract.