Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models
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- Maaya Morita
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Aki Yoneda
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Nagisa Tokunoh
- Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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- Tatsumi Masaki
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Keisuke Shirakura
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Mayumi Kinoshita
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Rina Hashimoto
- Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
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- Naoya Shigesada
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Junya Takahashi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Masashi Tachibana
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Shota Tanaka
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Masanori Obana
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Nobumasa Hino
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Masahito Ikawa
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Kazutake Tsujikawa
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Chikako Ono
- Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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- Yoshiharu Matsuura
- Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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- Hiroyasu Kidoya
- Department of Integrative Vascular Biology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
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- Nobuyuki Takakura
- Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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- Yoshiaki Kubota
- Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan
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- Takefumi Doi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Kazuo Takayama
- Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
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- Yasuo Yoshioka
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Yasushi Fujio
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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- Yoshiaki Okada
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
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説明
<jats:p>There is an urgent need to develop novel drugs to reduce the mortality from severe infectious diseases with the emergence of new pathogens, including Coronavirus disease 2019 (COVID-19). Although current drugs effectively suppress the proliferation of pathogens, immune cell activation, and inflammatory cytokine functions, they cannot completely reduce mortality from severe infections and sepsis. In this study, we focused on the endothelial cell-specific protein, Roundabout 4 (Robo4), which suppresses vascular permeability by stabilizing endothelial cells, and investigated whether enhanced Robo4 expression could be a novel therapeutic strategy against severe infectious diseases. Endothelial-specific overexpression of Robo4 suppresses vascular permeability and reduces mortality in lipopolysaccharide (LPS)-treated mice. Screening of small molecules that regulate Robo4 expression and subsequent analysis revealed that two competitive small mothers against decapentaplegic (SMAD) signaling pathways, activin receptor-like kinase 5 (ALK5)-SMAD2/3 and ALK1-SMAD1/5, positively and negatively regulate Robo4 expression, respectively. An ALK1 inhibitor was found to increase Robo4 expression in mouse lungs, suppress vascular permeability, prevent extravasation of melanoma cells, and decrease mortality in LPS-treated mice. The inhibitor suppressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced endothelial barrier disruption and decreased mortality in mice infected with SARS-CoV-2. These results indicate that enhancing Robo4 expression is an efficient strategy to suppress vascular permeability and mortality in severe infectious diseases, including COVID-19, and that small molecules that upregulate Robo4 can be potential therapeutic agents against these diseases.</jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 120 (3), 2023-01-12
Proceedings of the National Academy of Sciences
