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Clinical Track

Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

Kimio Satoh, Taiju Sato, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kota Suzuki, Koichiro Sugimura, Tatsuo Aoki, Kotaro Nochioka, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Masanobu Miura, Toru Shimizu, Shohei Ikeda, Nobuhiro Yaoita, Yoshihiro Fukumoto, Tatsuro Minami, Satoshi Miyata, Kazufumi Nakamura, Hiroshi Ito, Kenji Kadomatsu, Hiroaki Shimokawa
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https://doi.org/10.1161/CIRCRESAHA.115.304563
Circulation Research. 2014;CIRCRESAHA.114.304563
Originally published August 22, 2014
Kimio Satoh
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Taiju Sato
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Nobuhiro Kikuchi
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Junichi Omura
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Ryo Kurosawa
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Kota Suzuki
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Koichiro Sugimura
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Tatsuo Aoki
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Kotaro Nochioka
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Shunsuke Tatebe
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Saori Miyamichi-Yamamoto
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Masanobu Miura
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Toru Shimizu
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Shohei Ikeda
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Nobuhiro Yaoita
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Yoshihiro Fukumoto
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Tatsuro Minami
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Satoshi Miyata
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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Kazufumi Nakamura
Cardiovascular Medicine, Okayama University Graduate School of Medicine
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Hiroshi Ito
Cardiovascular Medicine, Okayama University Graduate School of Medicine
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Kenji Kadomatsu
Biochemistry, Nagoya University Graduate School of Medicine
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Hiroaki Shimokawa
Cardiovascular Medicine, Tohoku University Graduate School of Medicine
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  • For correspondence: shimo@cardio.med.tohoku.ac.jp
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Abstract

Rationale: Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated.

Objective: To determine the role of CyPA/Bsg signaling in the development of PH.

Methods and Results: In the pulmonary arteries (PA) of PH patients, immunostaining revealed strong expression of CyPA and Bsg. The PA of CyPA+/- and Bsg+/- mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA+/-and Bsg+/- mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure (RVSP), PA remodeling and RV hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from Bsg+/+ and Bsg+/- mice. Proliferation was significantly reduced in Bsg+/- compared with Bsg+/+ VSMCs. Mechanistic studies demonstrated that Bsg+/- VSMCs revealed reduced extracellular signal-regulated kinase (ERK)1/2 activation and less secretion of cytokines/chemokines and growth factors (e.g. PDGF-BB). Finally, in the clinical study, plasma CyPA levels in PH patients were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in PH patients.

Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.

  • hypoxia
  • oxidative stress
  • vascular smooth muscle
  • pulmonary hypertension
  • pulmonary circulation
  • inflammation
  • vascular remodeling
  • Received June 7, 2014.
  • Revision received August 21, 2014.
  • Accepted August 22, 2014.
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    Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
    Kimio Satoh, Taiju Sato, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kota Suzuki, Koichiro Sugimura, Tatsuo Aoki, Kotaro Nochioka, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Masanobu Miura, Toru Shimizu, Shohei Ikeda, Nobuhiro Yaoita, Yoshihiro Fukumoto, Tatsuro Minami, Satoshi Miyata, Kazufumi Nakamura, Hiroshi Ito, Kenji Kadomatsu and Hiroaki Shimokawa
    Circulation Research. 2014;CIRCRESAHA.114.304563, originally published August 22, 2014
    https://doi.org/10.1161/CIRCRESAHA.115.304563

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    Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation
    Kimio Satoh, Taiju Sato, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kota Suzuki, Koichiro Sugimura, Tatsuo Aoki, Kotaro Nochioka, Shunsuke Tatebe, Saori Miyamichi-Yamamoto, Masanobu Miura, Toru Shimizu, Shohei Ikeda, Nobuhiro Yaoita, Yoshihiro Fukumoto, Tatsuro Minami, Satoshi Miyata, Kazufumi Nakamura, Hiroshi Ito, Kenji Kadomatsu and Hiroaki Shimokawa
    Circulation Research. 2014;CIRCRESAHA.114.304563, originally published August 22, 2014
    https://doi.org/10.1161/CIRCRESAHA.115.304563
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  • Basic, Translational, and Clinical Research
    • Smooth Muscle Proliferation and Differentiation
    • Pulmonary Biology
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    • Growth Factors/Cytokines
    • Animal Models of Human Disease

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