Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

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 (PA) of PH patients, immunostaining revealed strong expression of CyPA and Bsg. The PA 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 (RVSP), PA remodeling and RV 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 (ERK)1/2 activation and less secretion of cytokines/chemokines and growth factors (e.g. PDGF-BB). Finally, in the clinical study, plasma CyPA levels in PH patients 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 PH patients.

Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.