HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells
| Autor: | Yoshiaki Okada, Maaya Morita, Masato Tanaka, Ryosuke Ishiba, Risa Funatsu, Mayumi Kinoshita, Taiki Aoshi, Tomoaki Kanbara, Ryo Suzuki, Nobumasa Hino, Taito Kashio, Shohei Koyama, Takefumi Doi, Yasuo Yoshioka, Kosuke Muraoka, Keisuke Shirakura |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Small interfering RNA Histology Pyridines Transcription factor complex Receptors Cell Surface Vascular permeability Biochemistry Capillary Permeability Mice 03 medical and health sciences 0302 clinical medicine Animals Transcription factor Gene knockdown Chemistry Endothelial Cells Cell migration Cell Biology HDAC3 Cell biology Histone Deacetylase Inhibitors Endothelial stem cell 030104 developmental biology Benzamides 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Tissue Barriers |
| ISSN: | 2168-8370 |
| DOI: | 10.1080/21688370.2021.1911195 |
| Popis: | Roundabout guidance receptor 4 (Robo4) is an endothelial-specific membrane protein that suppresses pathological angiogenesis and vascular hyperpermeability by stabilizing endothelial cells. Robo4 suppresses severe systemic inflammation induced by pathogens and endotoxins and inhibits tumor growth and metastasis, therefore serving as a potential therapeutic target. Although the regulation of Robo4 expression through transcription factors and epigenetic mechanisms has been studied, the role of histone deacetylases (HDACs) has not been explored. In the present study, we investigated the involvement of HDACs in the regulation of Robo4 expression. An HDAC inhibitor, MS-275, which inhibits HDAC1, HDAC2, and HDAC3, was found to suppress Robo4 expression in endothelial cells. Small interfering RNA (siRNA)-mediated knockdown of HDAC3, but not of HDAC1 and 2, also decreased its expression level. MS-275 downregulated the expression of the transcription factor complex GABP, in addition to suppressing Robo4 promoter activity. GABP expression was also downregulated by the siRNA against HDAC3. MS-275 decreased the transendothelial electrical resistance of a monolayer of mouse endothelial cells and increased the rate of leakage of Evans blue dye in the mouse lungs. In addition, MS-275 accelerated cell migration through the endothelial cell monolayer and augmented cell extravasation in the mouse lungs. Taken together, we demonstrated that MS-275 suppresses Robo4 expression by inhibiting HDAC3 in endothelial cells and enhances endothelial and vascular permeability. Thus, we demonstrated a novel mechanism regulating Robo4 expression and vascular permeability, which is anticipated to contribute to future therapies for infectious and inflammatory diseases. |
| Databáze: | OpenAIRE |
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