Abstract 14783: Cyclophilin a and Basigin Promotes Pulmonary Hypertension by Inducing Inflammation and Vascular Smooth Muscle Cell Proliferation
Introduction: Cyclophilin A (CyPA) is secreted from VSMCs by oxidative stress and promotes VSMC proliferation. However, the role of CyPA and its extracellular receptor Basigin (Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated.
Methods & Results: To determine the role of CyPA/Bsg signaling in PH development, CyPA+/- and Bsg+/- mice were exposed to hypoxia (O2 10%) for 4 weeks. The pulmonary arteries (PA) of CyPA+/- and Bsg+/- mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA+/- (n=12) and Bsg+/- mice (n=15) exposed to hypoxia revealed significantly reduced right ventricular systolic pressure (RVSP), PA remodeling and RV hypertrophy compared with their littermate controls (all P<0.01). Importantly, after transplantation of bone marrow, the severity of PH was still exacerbated in Bsg+/+ recipient mice compared with Bsg+/- recipient mice regardless of the source of bone marrow (Bsg+/+ or Bsg+/-), suggesting the crucial role of Bsg in PA. To further evaluate the role of Bsg, we harvested VSMCs from Bsg+/+ and Bsg+/- mice. Bsg expression in Bsg+/+ VSMCs was induced by extracellular CyPA, and was further augmented by hypoxia (O2 2%). The expression of NADPH oxidases (e.g. NOX2 and p47phox) was lower in Bsg+/- than in Bsg+/+ VSMCs. In contrast, Nrf2 and its downstream HO-1 were induced in Bsg+/- as compared with Bsg+/+ VSMCs. Additionally, the expression of BMPR2, which negatively regulates PDGF-BB and EGF in patients with PH, was induced in Bsg+/- VSMCs. Mechanistic studies demonstrated that Bsg+/- VSMCs revealed less secretion of cytokines/chemokines and growth factors (e.g. PDGF-BB). VSMC proliferation was significantly reduced in Bsg+/- compared with Bsg+/+ in response to 2% FBS, suggesting the crucial role of Bsg in VSMC proliferation. Finally, we examined CyPA-induced secretion of growth factors from VSMCs harvested from the PA of PH patients. Extracellular CyPA induced secretion of growth factors and chemokines (e.g. PDGF-BB, SDF-1, and FGF-2) and inflammatory cytokines (e.g. IL-1β, IL-2, and TNF-α) and this effect was enhanced by hypoxia (O2 2%).
Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.
Author Disclosures: K. Satoh: None. K. Suzuki: None. J. Omura: None. N. Kikuchi: None. S. Miyata: None. T. Minami: None. K. Sugimura: None. T. Aoki: None. K. Nochioka: None. S. Tatebe: None. M. Miura: None. S. Yamamoto: None. T. Shimizu: None. S. Ikeda: None. N. Yaoita: None. Y. Fukumoto: None. K. Nakamura: None. H. Ito: None. K. Kadomatsu: None. H. Shimokawa: None.
- © 2014 by American Heart Association, Inc.