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 ItoKenji Kadomatsu, Hiroaki Shimokawa

Research output: Contribution to journalArticle

52 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

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    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., ... 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