HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells

Kashio, Taito; Shirakura, Keisuke; Kinoshita, M.; Morita, Maaya; Ishiba, Ryosuke; Muraoka, Kosuke; Kanbara, Tomoaki; Tanaka, Masato; Funatsu, Risa; Hino, Nobumasa; Koyama, Shohei; Suzuki, Ryo; Yoshioka, Yasuo; Aoshi, Taiki; Doi, Takefumi; Okada, Yoshiaki

doi:10.1080/21688370.2021.1911195

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…MS-275 PC3 UP, 7614-21-3 CTD 00000893, troglitazone CTD, anisomycin PC3 UP, and 8-azaguanine PC3 UP were the top 5 valuable drugs. MS-275 is a speci c inhibitor of HDAC1 and belongs to the benzamide class [39]. It can selectively inhibit the rst class of HDACs, especially HDAC1, and regulate the acetylation levels of histones, thereby affecting the expression levels of tumor-related genes.…”

Section: Discussionmentioning

confidence: 99%

Network-based identification of the genetic mechanism behind acute lung injury in acute pancreatitis

Wan

Song

Pan

2022

Preprint

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Background Acute pancreatitis (AP) is a common gastrointestinal disease. The incidence of acute pancreatitis complicated with acute lung injury is high. In fact, the complication is the primary cause of early death in patients with acute pancreatitis. The purpose of this study was to clarify the genetic mechanism of acute pancreatitis complicated by lung injury using bioinformatics and to identify possible therapeutic drug options. Methods The dataset for acute pancreatitis, numbered GSE77983, and the dataset for acute lung injury, numbered GSE58654, were identified from the Gene Expression Ombibus (GEO) database. GEO2R was used to identify the common differentially expressed genes (DEGs). Gene ontology and pathway analyses were used to gain a comprehensive understanding of the role of DEGs. A protein interaction network from common DEGs was constructed using the STRING database to screen for hub genes. The transcription factors and miRNAs of hub genes were identified based on the NetworkAnalyst platform. Hub genes were validated at the human organ and single-cell levels. Finally, potential therapeutic compounds were designed. Results We found 61 common DEGs. The enrichment analysis showed that these genes were mainly concentrated in the cellular response to external stimuli, nutrient levels, and apoptosis. Fifteen hub genes were identified with a protein interaction network, and six hub genes (Angptl4, Cyr61, F3, Krt8, Sphk1, and Vcan) were verified at the single-cell and human tissue levels. At the single-cell level, the gene was shown to be mainly expressed in alveolar type I and II epithelial cells and mesothelial cells of the pancreas. Potential therapeutic compounds include MS-275 PC3 UP, 7614-21-3 CTD 00000893, troglitazone CTD, anisomycin PC3 UP, and 8-azaguanine PC3 UP. Conclusions Acute pancreatitis and acute lung injury co-express six hub genes, which may be the bridge to understanding the genetic mechanism of acute pancreatitis complicated with acute lung injury.

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Section: Discussionmentioning

confidence: 99%

Network-based identification of the genetic mechanism behind acute lung injury in acute pancreatitis

Wan

Song

Pan

2022

Preprint

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“…Another HDAC inhibitor, MS-275 [ 98 ], was found to effectively inhibit the activities of HDAC1, 2, and 3 [ 5 ]. Kashio [ 99 ] et al reported that MS-275 repressed HDAC3 activity in ECs, thereby suppressing the expression of roundabout guidance receptor 4 (Robo4) and inducing endothelial hyperpermeability and extravasation.…”

Section: Applications Of Hdac3 Inhibitorsmentioning

confidence: 99%

Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis

Jiang

Chen

et al. 2022

Aging and disease

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Atherosclerosis, the pathological basis of most cardiovascular disease, is characterized by plaque formation in the intima. Secondary lesions include intraplaque hemorrhage, plaque rupture, and local thrombosis. Vascular endothelial function impairment and smooth muscle cell migration lead to vascular dysfunction, which is conducive to the formation of macrophage-derived foam cells and aggravates inflammatory response and lipid accumulation that cause atherosclerosis. Histone deacetylase (HDAC) is an epigenetic modifying enzyme closely related to chromatin structure and gene transcriptional regulation. Emerging studies have demonstrated that the Class I member HDAC3 of the HDAC super family has cell-specific functions in atherosclerosis, including 1) maintenance of endothelial integrity and functions, 2) regulation of vascular smooth muscle cell proliferation and migration, 3) modulation of macrophage phenotype, and 4) influence on foam cell formation. Although several studies have shown that HDAC3 may be a promising therapeutic target, only a few HDAC3-selective inhibitors have been thoroughly researched and reported. Here, we specifically summarize the impact of HDAC3 and its inhibitors on vascular function, inflammation, lipid accumulation, and plaque stability in the development of atherosclerosis with the hopes of opening up new opportunities for the treatment of cardiovascular diseases.

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“…Robo4 stabilizes endothelial permeability by regulating both adherens junctions and tight junctions in endothelial cells. 29,32,33) Adherens junctions are involved in the transmigration of cancer and immune cells, [34][35][36] and lack of Robo4 enhances lung metastasis of cancers 24,37) and diapedesis of immune cells. 29) In vitro studies have shown that Robo4 suppresses endothelial hyperpermeability induced by various stimuli such as vascular endothelial growth factor (VEGF), 22,38) interleukin-1β (IL-1β), 31) tumor necrosis factor α (TNF-α), 29,31) and histamine.…”

Section: Robo4 Suppresses Vascular Leakage Under Pathological Conditionsmentioning

confidence: 99%

Vascular Leakage Prevention by Roundabout 4 under Pathological Conditions

Shirakura

Okada

2021

Biological & Pharmaceutical Bulletin

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Vascular permeability is regulated mainly by the endothelial barrier and controls vascular homeostasis, proper vessel development, and immune cell trafficking. Several molecules are involved in regulating endothelial barrier function. Roundabout 4 (Robo4) is a single-pass transmembrane protein that is specifically expressed in vascular endothelial cells. Robo4 is an important regulator of vascular leakage and angiogenesis, especially under pathological conditions. The role of Robo4 in preventing vascular leakage has been studied in various disease models, including animal models of retinopathy, tumors, diabetes, and endotoxemia. The involvement of Robo4 in vascular endothelial growth factor and inflammation-mediated signaling pathways has been well studied, and recent evidence suggests that Robo4 modulates endothelial barrier function via distinct mechanisms. In this review, we discuss the role of Robo4 in endothelial barrier function and the underlying molecular mechanisms.

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HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells

Cited by 11 publications

References 26 publications

Network-based identification of the genetic mechanism behind acute lung injury in acute pancreatitis

Network-based identification of the genetic mechanism behind acute lung injury in acute pancreatitis

Histone Deacetylase 3: A Potential Therapeutic Target for Atherosclerosis

Vascular Leakage Prevention by Roundabout 4 under Pathological Conditions

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