1. Academic Validation
  2. 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

  • Cell Commun Signal. 2021 Mar 18;19(1):35. doi: 10.1186/s12964-020-00681-z.
Shuai Huang  # 1 2 Gen Chen  # 2 Jia Sun 2 Yunjie Chen 2 Nan Wang 2 Yetong Dong 2 Enzhao Shen 2 Zhicheng Hu 2 Wenjie Gong 2 Litai Jin 3 Weitao Cong 4
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
  • 2 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China.
  • 3 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China. jin_litai@126.com.
  • 4 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, People's Republic of China. cwt97126@126.com.
  • # Contributed equally.
Abstract

Background: 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.

Methods: 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.

Results: 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.

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

Keywords

Endothelial dysfunction; HDAC3; Nrf2; T2DM.

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