Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin

Daisuke Kinoshita; Tetsuro Shishido; Tetsuya Takahashi; Miyuki Yokoyama; Takayuki Sugai; Ken Watanabe; Harutoshi Tamura; Satoshi Nishiyama; Hiroki Takahashi; Takanori Arimoto; Takuya Miyamoto; Tetsu Watanabe; Satoshi Kishida; Kenji Kadomatsu; Jun ichi Abe; Yasuchika Takeishi; Tsuneo Konta; Isao Kubota; Masafumi Watanabe

doi:10.1038/s41598-020-67217-w

Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin

Daisuke Kinoshita, Tetsuro Shishido, Tetsuya Takahashi, Miyuki Yokoyama, Takayuki Sugai, Ken Watanabe, Harutoshi Tamura, Satoshi Nishiyama, Hiroki Takahashi, Takanori Arimoto, Takuya Miyamoto, Tetsu Watanabe, Satoshi Kishida, Kenji Kadomatsu, Jun ichi Abe, Yasuchika Takeishi, Tsuneo Konta, Isao Kubota, Masafumi Watanabe

Cardiology

Research output: Contribution to journal › Article › peer-review

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Abstract

Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

Original language	English (US)
Article number	10345
Journal	Scientific reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-67217-w
State	Published - Dec 1 2020

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Kinoshita, D., Shishido, T., Takahashi, T., Yokoyama, M., Sugai, T., Watanabe, K., Tamura, H., Nishiyama, S., Takahashi, H., Arimoto, T., Miyamoto, T., Watanabe, T., Kishida, S., Kadomatsu, K., Abe, J. I., Takeishi, Y., Konta, T., Kubota, I., & Watanabe, M. (2020). Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin. Scientific reports, 10(1), Article 10345. https://doi.org/10.1038/s41598-020-67217-w

Kinoshita, D, Shishido, T, Takahashi, T, Yokoyama, M, Sugai, T, Watanabe, K, Tamura, H, Nishiyama, S, Takahashi, H, Arimoto, T, Miyamoto, T, Watanabe, T, Kishida, S, Kadomatsu, K, Abe, JI, Takeishi, Y, Konta, T, Kubota, I & Watanabe, M 2020, 'Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin', Scientific reports, vol. 10, no. 1, 10345. https://doi.org/10.1038/s41598-020-67217-w

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abstract = "Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.",

author = "Daisuke Kinoshita and Tetsuro Shishido and Tetsuya Takahashi and Miyuki Yokoyama and Takayuki Sugai and Ken Watanabe and Harutoshi Tamura and Satoshi Nishiyama and Hiroki Takahashi and Takanori Arimoto and Takuya Miyamoto and Tetsu Watanabe and Satoshi Kishida and Kenji Kadomatsu and Abe, {Jun ichi} and Yasuchika Takeishi and Tsuneo Konta and Isao Kubota and Masafumi Watanabe",

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doi = "10.1038/s41598-020-67217-w",

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AU - Kinoshita, Daisuke

AU - Shishido, Tetsuro

AU - Takahashi, Tetsuya

AU - Yokoyama, Miyuki

AU - Sugai, Takayuki

AU - Watanabe, Ken

AU - Tamura, Harutoshi

AU - Nishiyama, Satoshi

AU - Takahashi, Hiroki

AU - Arimoto, Takanori

AU - Miyamoto, Takuya

AU - Watanabe, Tetsu

AU - Kishida, Satoshi

AU - Kadomatsu, Kenji

AU - Abe, Jun ichi

AU - Takeishi, Yasuchika

AU - Konta, Tsuneo

AU - Kubota, Isao

AU - Watanabe, Masafumi

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

AB - Pulmonary arterial hypertension (PAH) is a progressive fatal disease caused by pulmonary arterial remodeling. Midkine regulates cell proliferation and migration, and it is induced by hypoxia, but its roles in pulmonary arterial remodeling remain unclear. Serum midkine levels were significantly increased in PAH patients compared with control patients. Midkine expression was increased in lungs and sera of hypoxia-induced PAH mice. Hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy were attenuated in midkine-knockout mice. Midkine-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMC) and epidermal growth factor receptor (EGFR) signaling were significantly increased under hypoxia, which also induced cell-surface translocation of nucleolin. Nucleolin siRNA treatment suppressed midkine-induced EGFR activation in vitro, and nucleolin inhibitor AS1411 suppressed proliferation and migration of PASMC induced by midkine. Furthermore, AS1411 significantly prevented the development of PAH in Sugen hypoxia rat model. Midkine plays a crucial role in PAH development through interaction with surface nucleolin. These data define a role for midkine in PAH development and suggest midkine-nucleolin-EGFR axis as a novel therapeutic target for PAH.

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Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin

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