1. Academic Validation
  2. HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells

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

  • Tissue Barriers. 2021 Jul 3;9(3):1911195. doi: 10.1080/21688370.2021.1911195.
Taito Kashio 1 Keisuke Shirakura 1 Mayumi Kinoshita 1 Maaya Morita 1 Ryosuke Ishiba 1 Kosuke Muraoka 1 Tomoaki Kanbara 1 Masato Tanaka 1 Risa Funatsu 1 Nobumasa Hino 1 Shohei Koyama 2 Ryo Suzuki 3 4 Yasuo Yoshioka 1 5 6 Taiki Aoshi 7 Takefumi Doi 1 Yoshiaki Okada 1
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 2 Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
  • 3 Laboratory of Drug and Gene Delivery Research, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan.
  • 4 Advanced Comprehensive Research Organization, Teikyo University, Tokyo, Japan.
  • 5 Vaccine Creation Group, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
  • 6 BIKEN Center for Innovative Vaccine Research and Development, the Research Foundation for Microbial Diseases of Osaka University, Osaka, Japan.
  • 7 Department of Cellular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Abstract

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.

Keywords

HDAC3; MS-275; adherens junction; endothelial cells; roundabout 4.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16914
    HDAC抑制剂