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

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.

• Authors: Shuai Huang, Gen Chen, Jia Sun, Yunjie Chen, Nan Wang, Yetong Dong, Enzhao Shen, Zhicheng Hu, Wenjie Gong, Litai Jin, Weitao Cong
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 19 Issue 1 Pg. 35 (03 18 2021) ISSN: 1478-811X [Electronic] England
• PMID: 33736642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Protective Agents
• NADPH Oxidase 4
• Nox4 protein, mouse
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Diabetes Mellitus (pathology)
• Endothelium, Vascular (drug effects, metabolism, pathology, physiopathology)
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, metabolism)
• Humans
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• Mice, Inbred C57BL
• NADPH Oxidase 4 (antagonists & inhibitors, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Protective Agents (pharmacology)
• Protein Binding (drug effects)