Histone deacetylases and atherosclerosis

Zheng, Xia-Xia; Zhou, Tian; Wang, Xinan; Tong, Xiaohong; Ding, Jiawang

doi:10.1016/j.atherosclerosis.2014.12.048

Cited by 47 publications

(29 citation statements)

References 175 publications

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“…Emerging evidence indicates that HDAC-dependent epigenetic mechanisms play an important role in mediating cell proliferation, migration, and apoptosis, oxidative stress and inflammatory reactions in several experimental models of CVD [29] , [30] . Thus far, the impact of diabetic conditions on vascular HDAC system and its potential implication in the regulation of Nox enzymes have not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

et al. 2018

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Reactive oxygen species (ROS) generated by up-regulated NADPH oxidase (Nox) contribute to structural-functional alterations of the vascular wall in diabetes. Epigenetic mechanisms, such as histone acetylation, emerged as important regulators of gene expression in cardiovascular disorders. Since their role in diabetes is still elusive we hypothesized that histone deacetylase (HDAC)-dependent mechanisms could mediate vascular Nox overexpression in diabetic conditions. Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive vehicle or suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor. In vitro studies were performed on a human aortic smooth muscle cell (SMC) line. Aortic SMCs typically express Nox1, Nox4, and Nox5 subtypes. HDAC1 and HDAC2 proteins along with Nox1, Nox2, and Nox4 levels were found significantly elevated in the aortas of diabetic mice compared to non-diabetic animals. Treatment of diabetic mice with SAHA mitigated the aortic expression of Nox1, Nox2, and Nox4 subtypes and NADPH-stimulated ROS production. High concentrations of glucose increased HDAC1 and HDAC2 protein levels in cultured SMCs. SAHA significantly reduced the high glucose-induced Nox1/4/5 expression, ROS production, and the formation malondialdehyde-protein adducts in SMCs. Overexpression of HDAC2 up-regulated the Nox1/4/5 gene promoter activities in SMCs. Physical interactions of HDAC1/2 and p300 proteins with Nox1/4/5 promoters were detected at the sites of active transcription. High glucose induced histone H3K27 acetylation enrichment at the promoters of Nox1/4/5 genes in SMCs. The novel data of this study indicate that HDACs mediate vascular Nox up-regulation in diabetes. HDAC inhibition reduces vascular ROS production in experimental diabetes, possibly by a mechanism involving negative regulation of Nox expression.

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Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

et al. 2018

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“…K Ca 3.1 is a potential therapeutic target for not only IBD, but also for other autoimmune disorders, asthma, atherosclerosis, and fibrosis [ 2 , 4 ]. Similarly, HDAC2 and HDAC3 are key regulators of the following disorders: rheumatoid arthritis [ 42 ], severe asthma and chronic obstructive pulmonary disease [ 43 , 44 , 45 ], and atherosclerosis [ 46 , 47 ]. The contribution of HDAC2 to tissue fibrosis is attracting increasing attention [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

Matsui

Terasawa

Kajikuri

et al. 2018

IJMS

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The up-regulated expression of the Ca2+-activated K+ channel KCa3.1 in inflammatory CD4+ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD) through the enhanced production of inflammatory cytokines, such as interferon-γ (IFN-γ). However, the underlying mechanisms have not yet been elucidated. The objective of the present study is to clarify the involvement of histone deacetylases (HDACs) in the up-regulation of KCa3.1 in the CD4+ T cells of IBD model mice. The expression levels of KCa3.1 and its regulators, such as function-modifying molecules and transcription factors, were quantitated using a real-time polymerase chain reaction (PCR) assay, Western blotting, and depolarization responses, which were induced by the selective KCa3.1 blocker TRAM-34 (1 μM) and were measured using a voltage-sensitive fluorescent dye imaging system. The treatment with 1 μM vorinostat, a pan-HDAC inhibitor, for 24 h repressed the transcriptional expression of KCa3.1 in the splenic CD4+ T cells of IBD model mice. Accordingly, TRAM-34-induced depolarization responses were significantly reduced. HDAC2 and HDAC3 were significantly up-regulated in the CD4+ T cells of IBD model mice. The down-regulated expression of KCa3.1 was observed following treatments with the selective inhibitors of HDAC2 and HDAC3. The KCa3.1 K+ channel regulates inflammatory cytokine production in CD4+ T cells, mediating epigenetic modifications by HDAC2 and HDAC3.

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“…Furthermore, pharmacological inhibition of HDAC6 in macrophages has been shown to protect against lipopolysaccharide-induced inflammation by reducing deacetylation of microtubules (35). A recent review by Zheng et al summarizes current knowledge of the roles of HDACs in atherosclerosis and raises an important question regarding whether HDAC6 is an important negative regulator of vasculature contractile function that leads to the progression of atherosclerosis (41).…”

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confidence: 99%

Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

Leucker

Nomura

Kim

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of HS. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the HS donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and HS production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.

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Histone deacetylases and atherosclerosis

Cited by 47 publications

References 175 publications

Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

Epigenetic regulation of vascular NADPH oxidase expression and reactive oxygen species production by histone deacetylase-dependent mechanisms in experimental diabetes

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

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