Kimio Satoh1, Taijyu Satoh1, Nobuhiro Kikuchi1, Junichi Omura1, Ryo Kurosawa1, Kota Suzuki1, Koichiro Sugimura1, Tatsuo Aoki1, Kotaro Nochioka1, Shunsuke Tatebe1, Saori Miyamichi-Yamamoto1, Masanobu Miura1, Toru Shimizu1, Shohei Ikeda1, Nobuhiro Yaoita1, Yoshihiro Fukumoto1, Tatsuro Minami1, Satoshi Miyata1, Kazufumi Nakamura1, Hiroshi Ito1, Kenji Kadomatsu1, Hiroaki Shimokawa2. 1. 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.). 2. 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.
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.
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.
Authors: Ling Yan; Xinping Chen; Megha Talati; Bethany Womack Nunley; Santhi Gladson; Tom Blackwell; Joy Cogan; Eric Austin; Ferrin Wheeler; James Loyd; James West; Rizwan Hamid Journal: Am J Respir Crit Care Med Date: 2016-04-15 Impact factor: 21.405