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.

Role of Histone Post-Translational Modifications in Inflammatory Diseases

“…Selective inhibition of HDAC3 by RGFP966 enhanced insulin secretion and synthesis which might retard the development of T2D ( 114 ). In addition, inhibition of HDAC3 accelerates vascular endothelial proliferation during vascular impairment caused by T2D through activating Nrf2 signaling by inhibiting Keap1 synthesis and Nrf2–Nox4 association, which indicated the potential of HDAC3 as an epigenetic regulator in T2D-related vascular complications ( 16 ). Elevated levels of HDAC7 lead to β cell dysfunction and the defects of T2D ( 115 ).…”

The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases

“…In recent years, seven NOXs isoform (NOX1-NOX5, dual oxidase 1 (DUOX1), and DUOX2) have been identified [ 63 ]. Silencing of HDAC3 impairs the interaction of KEAP1 and Nrf2, increasing the Nrf2 level, resulting in a decrease of NOX4 [ 15 ]. Consistently, the knockdown of HDAC3 in vitro represses the combination of transcription factors and polymerases with the NOX4 promoter, thereby inhibiting transcription of NOX4 and production of NOX4 associated ROS in human endothelial cells [ 64 ].…”

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson’s Disease

“…For example, increasing the NAD + /NADH ratio has been shown to activate AMPK [ 7 ], which stimulates mitophagy [ 8 ]. As another example, increased NADPH has been shown to inhibit histone deacetylase 3 (HDAC3) [ 9 ], and HDAC3 inhibition has been shown to increase autophagy [ 10 ] and elevate Nrf2 transcriptional activity and the antioxidant response [ 11 ]. In contrast to its effect on HDAC3, NADPH stimulates HDAC1 and HDAC2 activity [ 12 ].…”