LncRNA NORAD Promotes Vascular Endothelial Cell Injury and Atherosclerosis Through Suppressing VEGF Gene Transcription via Enhancing H3K9 Deacetylation by Recruiting HDAC6

Kai, Huihua; Wu, Qiyong; Yin, Ruohan; Tang, Xiaoqiang; Shi, Haifeng; Wang, Tao; Zhang, Ming; Pan, Changjie

doi:10.3389/fcell.2021.701628

Cited by 20 publications

(28 citation statements)

References 50 publications

(55 reference statements)

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“…Epicardial adipose tissue (EAT) may target HDAC4 and cause endothelial cell damage induced by miR-200b-3p, promoting oxidative stress ( 9 ). LncRNA non-coding RNA activated by DNA damage (NORAD) is a novel long non-coding RNA (lncRNA); it could recruit HDAC6 to enhance H3K9 deacetylation and consequently suppress the transcription of the VFGF gene which was supposed to enhance vascular endothelial cell injury and atherosclerosis ( 10 ). Endothelial–mesenchymal transition (EndMT) is associated with atherosclerosis and plaque instability.…”

Section: Histone Modifications In Inflammatory Diseasesmentioning

confidence: 99%

Role of Histone Post-Translational Modifications in Inflammatory Diseases

et al. 2022

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Inflammation is a defensive reaction for external stimuli to the human body and generally accompanied by immune responses, which is associated with multiple diseases such as atherosclerosis, type 2 diabetes, Alzheimer’s disease, psoriasis, asthma, chronic lung diseases, inflammatory bowel disease, and multiple virus-associated diseases. Epigenetic mechanisms have been demonstrated to play a key role in the regulation of inflammation. Common epigenetic regulations are DNA methylation, histone modifications, and non-coding RNA expression; among these, histone modifications embrace various post-modifications including acetylation, methylation, phosphorylation, ubiquitination, and ADP ribosylation. This review focuses on the significant role of histone modifications in the progression of inflammatory diseases, providing the potential target for clinical therapy of inflammation-associated diseases.

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Section: Histone Modifications In Inflammatory Diseasesmentioning

confidence: 99%

Role of Histone Post-Translational Modifications in Inflammatory Diseases

et al. 2022

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“…At the same time, the lncRNA NORAD knockdown alleviated vascular endothelial cell injury and atherosclerosis development in both models (in vitro and in vivo). In ox-LDL-treated HUVECs, VEGF gene transcription was suppressed by nucleus lncRNA NORAD enhancing H3K9 deacetylation and recruiting HDAC6 (Histone Deacetylase 6) to the VEGF gene promoter [62]. In addition to lncRNA, an ability to regulate VEGF-A was proven for circRNA (circular RNAs) originated from 6-8 exons of the LMF1 (lipase maturation factor 1).…”

Section: Atherosclerosismentioning

confidence: 99%

The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets

Dabravolski

Khotina

Omelchenko

et al. 2022

IJMS

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The vascular endothelial growth factor (VEGF) family, the crucial regulator of angiogenesis, lymphangiogenesis, lipid metabolism and inflammation, is involved in the development of atherosclerosis and further CVDs (cardiovascular diseases). This review discusses the general regulation and functions of VEGFs, their role in lipid metabolism and atherosclerosis development and progression. These functions present the great potential of applying the VEGF family as a target in the treatment of atherosclerosis and related CVDs. In addition, we discuss several modern anti-atherosclerosis VEGFs-targeted experimental procedures, drugs and natural compounds, which could significantly improve the efficiency of atherosclerosis and related CVDs’ treatment.

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“…Treatment with anti-HDAC6 showed significantly enriched binding of HDAC6 to the miR-155-5p promoter regions compared with the control (Figure 3F,G). It is well-known that HDAC6 could deacetylate H3K9, and H3K9 deacetylation at the promoter usually results in reduced transcription [21,25,43]. Therefore, we then performed ChIP assays with Ac-H3K9 in the context of HDAC6 knockdown in bEnd.3 cells.…”

Section: Hdac6 Inhibition Increases Intranuclear Histone Expression and Increases Mir-155-5p Expression In Microvascular Endothelial Cellmentioning

confidence: 99%

“…In addition to the well-known regulation of EC migration, HDAC6 has recently been reported to regulate EC proliferation. HDAC6 recruitment enhances EC injury and atherosclerosis by inhibiting vascular endothelial growth factor (VEGF) gene transcription in human umbilical vein endothelial cells (HUVECs) [ 21 ]. Furthermore, silencing HDAC6 inhibited proliferation and vasoformation of HUVECs, indicating that HDAC6 is involved in angiogenesis through EC proliferation [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, it is still unclear whether the expression of HDAC6 changes under mechanical unloading and what the role of HDAC6 in microvascular endothelial cells is. Recent studies have shown that HDAC6 serves as a crucial regulator in chromatin maintenance and function by regulating histone acetylation [ 21 , 23 ]. In addition to directly regulating mRNA gene expression, the inhibition of HDAC6 activity has been shown to regulate microRNA (miRNA) expression in a variety of human diseases.…”

Section: Introductionmentioning

confidence: 99%

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HDAC6 Negatively Regulates miR-155-5p Expression to Elicit Proliferation by Targeting RHEB in Microvascular Endothelial Cells under Mechanical Unloading

Zhang

et al. 2021

IJMS

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Mechanical unloading contributes to significant cardiovascular deconditioning. Endothelial dysfunction in the sites of microcirculation may be one of the causes of the cardiovascular degeneration induced by unloading, but the detailed mechanism is still unclear. Here, we first demonstrated that mechanical unloading inhibited brain microvascular endothelial cell proliferation and downregulated histone deacetylase 6 (HDAC6) expression. Furthermore, HDAC6 promoted microvascular endothelial cell proliferation and attenuated the inhibition of proliferation caused by clinorotation unloading. To comprehensively identify microRNAs (miRNAs) that are regulated by HDAC6, we analyzed differential miRNA expression in microvascular endothelial cells after transfection with HDAC6 siRNA and selected miR-155-5p, which was the miRNA with the most significantly increased expression. The ectopic expression of miR-155-5p inhibited microvascular endothelial cell proliferation and directly downregulated Ras homolog enriched in brain (RHEB) expression. Moreover, RHEB expression was downregulated under mechanical unloading and was essential for the miR-155-5p-mediated promotion of microvascular endothelial cell proliferation. Taken together, these results are the first to elucidate the role of HDAC6 in unloading-induced cell growth inhibition through the miR-155-5p/RHEB axis, suggesting that the HDAC6/miR-155-5p/RHEB pathway is a specific target for the preventative treatment of cardiovascular deconditioning.

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LncRNA NORAD Promotes Vascular Endothelial Cell Injury and Atherosclerosis Through Suppressing VEGF Gene Transcription via Enhancing H3K9 Deacetylation by Recruiting HDAC6

Cited by 20 publications

References 50 publications

Role of Histone Post-Translational Modifications in Inflammatory Diseases

Role of Histone Post-Translational Modifications in Inflammatory Diseases

The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets

HDAC6 Negatively Regulates miR-155-5p Expression to Elicit Proliferation by Targeting RHEB in Microvascular Endothelial Cells under Mechanical Unloading

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