Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation

Kimio Satoh, Taijyu Satoh, 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 Itoh & 2 others Kenji Kadomatsu, Hiroaki Shimokawa

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries 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, pulmonary artery remodeling, and right ventricular 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 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH 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 patients with PH. Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.

Original languageEnglish
Pages (from-to)738-750
Number of pages13
JournalCirculation Research
Volume115
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

CD147 Antigens
Cyclophilin A
Vascular Smooth Muscle
Pulmonary Hypertension
Smooth Muscle Myocytes
Cell Proliferation
Inflammation
Pulmonary Artery
Blood Vessels
Right Ventricular Hypertrophy
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Ventricular Pressure
Chemokines
Vascular Resistance
Intercellular Signaling Peptides and Proteins
Oxidative Stress
Bone Marrow

Keywords

  • Anoxia
  • Hypertension, pulmonary
  • Inflammation
  • Muscle, smooth, vascular
  • Oxidative stress
  • Pulmonary circulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Satoh, K., Satoh, T., Kikuchi, N., Omura, J., Kurosawa, R., Suzuki, K., ... Shimokawa, H. (2014). Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. Circulation Research, 115(8), 738-750. https://doi.org/10.1161/CIRCRESAHA.115.304563

Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. / Satoh, Kimio; Satoh, Taijyu; Kikuchi, Nobuhiro; Omura, Junichi; Kurosawa, Ryo; Suzuki, Kota; Sugimura, Koichiro; Aoki, Tatsuo; Nochioka, Kotaro; Tatebe, Shunsuke; Miyamichi-Yamamoto, Saori; Miura, Masanobu; Shimizu, Toru; Ikeda, Shohei; Yaoita, Nobuhiro; Fukumoto, Yoshihiro; Minami, Tatsuro; Miyata, Satoshi; Nakamura, Kazufumi; Itoh, Hiroshi; Kadomatsu, Kenji; Shimokawa, Hiroaki.

In: Circulation Research, Vol. 115, No. 8, 2014, p. 738-750.

Research output: Contribution to journalArticle

Satoh, K, Satoh, T, Kikuchi, N, Omura, J, Kurosawa, R, Suzuki, K, Sugimura, K, Aoki, T, Nochioka, K, Tatebe, S, Miyamichi-Yamamoto, S, Miura, M, Shimizu, T, Ikeda, S, Yaoita, N, Fukumoto, Y, Minami, T, Miyata, S, Nakamura, K, Itoh, H, Kadomatsu, K & Shimokawa, H 2014, 'Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation', Circulation Research, vol. 115, no. 8, pp. 738-750. https://doi.org/10.1161/CIRCRESAHA.115.304563
Satoh, Kimio ; Satoh, Taijyu ; Kikuchi, Nobuhiro ; Omura, Junichi ; Kurosawa, Ryo ; Suzuki, Kota ; Sugimura, Koichiro ; Aoki, Tatsuo ; Nochioka, Kotaro ; Tatebe, Shunsuke ; Miyamichi-Yamamoto, Saori ; Miura, Masanobu ; Shimizu, Toru ; Ikeda, Shohei ; Yaoita, Nobuhiro ; Fukumoto, Yoshihiro ; Minami, Tatsuro ; Miyata, Satoshi ; Nakamura, Kazufumi ; Itoh, Hiroshi ; Kadomatsu, Kenji ; Shimokawa, Hiroaki. / Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. In: Circulation Research. 2014 ; Vol. 115, No. 8. pp. 738-750.
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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 of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries 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, pulmonary artery remodeling, and right ventricular 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 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH 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 patients with PH. Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.",
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author = "Kimio Satoh and Taijyu Satoh and Nobuhiro Kikuchi and Junichi Omura and Ryo Kurosawa and Kota Suzuki and Koichiro Sugimura and Tatsuo Aoki and Kotaro Nochioka and Shunsuke Tatebe and Saori Miyamichi-Yamamoto and Masanobu Miura and Toru Shimizu and Shohei Ikeda and Nobuhiro Yaoita and Yoshihiro Fukumoto and Tatsuro Minami and Satoshi Miyata and Kazufumi Nakamura and Hiroshi Itoh and Kenji Kadomatsu and Hiroaki Shimokawa",
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T1 - Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation

AU - Satoh, Kimio

AU - Satoh, Taijyu

AU - Kikuchi, Nobuhiro

AU - Omura, Junichi

AU - Kurosawa, Ryo

AU - Suzuki, Kota

AU - Sugimura, Koichiro

AU - Aoki, Tatsuo

AU - Nochioka, Kotaro

AU - Tatebe, Shunsuke

AU - Miyamichi-Yamamoto, Saori

AU - Miura, Masanobu

AU - Shimizu, Toru

AU - Ikeda, Shohei

AU - Yaoita, Nobuhiro

AU - Fukumoto, Yoshihiro

AU - Minami, Tatsuro

AU - Miyata, Satoshi

AU - Nakamura, Kazufumi

AU - Itoh, Hiroshi

AU - Kadomatsu, Kenji

AU - Shimokawa, Hiroaki

PY - 2014

Y1 - 2014

N2 - 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 of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries 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, pulmonary artery remodeling, and right ventricular 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 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH 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 patients with PH. Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.

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KW - Anoxia

KW - Hypertension, pulmonary

KW - Inflammation

KW - Muscle, smooth, vascular

KW - Oxidative stress

KW - Pulmonary circulation

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