title: Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Taijyu
authors.initials: T
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sugimura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Aoki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kotaro
authors.initials: K
authors.lastname: Nochioka
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tatebe
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Saori
authors.initials: S
authors.lastname: Miyamichi-Yamamoto
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Masanobu
authors.initials: M
authors.lastname: Miura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yaoita
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Minami
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K. Satoh, T.S., N.K., J.O., R.K., K. Suzuki, K. Sugimura, T.A., K.N., S.T., S.M.-Y., M.M., T.S., S.I., N.Y., Y.F., T.M., S.M., H.S.); Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Okayama City, Japan (K.N., H.I.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.). shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D021984:Cyclophilin A / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology
chemical_list: D018925:Chemokines; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D051926:Basigin; D048049:Extracellular Signal-Regulated MAP Kinases; D021984:Cyclophilin A
keywords: anoxia; hypertension, pulmonary; inflammation; muscle, smooth, vascular; oxidative stress; pulmonary circulation