Involvement of the Antioxidant Effect and Anti-inflammatory Response in Butyrate-Inhibited Vascular Smooth Muscle Cell Proliferation

Abstract

Epigenetic mechanisms by altering the expression and, in turn, functions of target genes have potential to modify cellular processes that are characteristics of atherosclerosis, including inflammation, proliferation, migration and apoptosis/cell death. Butyrate, a natural epigenetic modifier and a histone deacetylase inhibitor (HDACi), is an inhibitor of vascular smooth muscle cell (VSMC) proliferation, a critical event in atherogenesis. Here, we examined whether glutathione peroxidases (GPxs), a family of antioxidant enzymes, are modulated by butyrate, contributing to its antiproliferation action on VSMC through the regulation of the inflammatory response by using western blotting, immunostaining methods and activity assay. Treatment of VSMC with butyrate not only upregulates glutathione peroxidase (GPx) 3 and GPx4, but also increases the overall catalytic activity of GPx supporting involvement of antioxidant effect in butyrate arrested VSMC proliferation. Moreover, analysis of the redox-sensitive NF-κB transcription factor system, the target of GPx, reveals that butyrate causes downregulation of IKKα, IKKβ, IkBα and NF-κBp65 expression and prevents NF-κBp65 phosphorylation at serine536 causing inhibition of the expression NF-κB target inflammatory genes, including inducible nitric oxide synthase, VCAM-1 and cyclooxygenase-2. Overall, these observations suggest a link between the antioxidant effect and anti-inflammatory response in butyrate-arrested VSMC proliferation, accentuating the atheroprotective and therapeutic potential of natural products, like butyrate, in vascular proliferative diseases.

Reduced expression of the ferroptosis inhibitor glutathione peroxidase‐4 in multiple sclerosis and experimental autoimmune encephalomyelitis

“…Indeed, upregulation of total GPx4 in vascular smooth muscle cells by butyrate causes a time‐dependent increase in the nuclear localization of this protein and almost complete disappearance from the cytoplasm (Mathew et al . ). Moreover, overexpression of c‐GPx4 in Gpx4 ‐null mice leads to an accumulation of this protein in mitochondria despite the absence of the mitochondrial signal peptide (Liang et al .…”

Histone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia‐induced cell growth

“…HDAC inhibitors block this action and thereby affect gene expression. HDIs modulate the histone modification pattern and generate a novel genomic expression profile in VSMCs . To further confirm the induction of eNOS by HDIs and explore its mechanism, we examined the acetylation of histones H3 and H4 on the eNOS promoter region under Bur treatment.…”

“…HDIs are a group of proteins that regulate histone acetylation in nucleosomes and mediate changes in chromatin conformation, leading to the regulation of gene expression . Accumulating evidence shows that HDIs modulate histone acetylation states for the transcriptional control of proliferative genes such as p21 and p27 . However, the epigenetic mechanism involved in the HDI‐mediated suppression of VSMC proliferation is not completely understood.…”

Lingonberries reduce atherosclerosis in Apoe‐/‐ mice in association with altered gut microbiota composition and improved lipid profile

“…A. muciniphila, likely played a greater role for the observed effects on host lipid metabolism. Furthermore, E. dolichum is a butyrate‐producing bacterium and butyrate has anti‐inflammatory properties and can reduce proliferation of vascular smooth muscle cells in vitro .…”