Abstract 11189: Plasma Cyclophilin A as a Novel Biomarker for Pulmonary Hypertension in Humans
Background: Pulmonary hypertension(PH) is associated with hypoxic exposure, enhanced production of reactive oxygen species (ROS) and proliferation of vascular smooth muscle cells(VSMC). We have recently demonstrated that ROS stimulate secretion of VSMC-derived cyclophilin A (CyPA) that promotes proliferation and migration of VSMC. In this study, we tested our hypothesis that CyPA contributes to pulmonary vascular remodeling in patients with PH.
Methods and Results: We used lung tissue and pulmonary artery VSMC from 8 PH patients who underwent lung transplantation and 6 controls. Immunostaining of the lung revealed strong CyPA expression in pulmonary VSMC of the PH patients. Organ culture experiments showed that CyPA secretion from the lung was significantly increased in the PH patients compared with the controls (P<0.01). In cultured human pulmonary arterial VSMC, hypoxia (O2 2%) significantly increased CyPA secretion compared with normoxic condition (O2 21%). The extent of the hypoxia-induced CyPA secretion was significantly enhanced in PH VSMC compared with control VSMC (P<0.0001), which was significantly inhibited by a specific Rho-kinase inhibitor, hydroxyfasudil (P<0.001). In contrast, combination of chronic hypoxia (O2 2%) and human recombinant CyPA significantly increased ERK1/2 phosphorylation and the expression of EMMPRIN (Basigin, CD147) in PH VSMC, which is a receptor for extracellular CyPA. Importantly, plasma CyPA levels were significantly elevated in patients with PH (16.1±12.1, n=109) than in those without PH (9.4±7.5, n=37, P=0.003) or healthy controls (3.9±3.0, n=23, P<0.0001). Moreover, plasma CyPA levels increased according to the quartiles of pulmonary vascular resistance (PVR, P<0.001). In contrast, PVR increased according to the quartiles of plasma CyPA (P<0.001). Medical treatments reduced plasma CyPA levels in patients with PH, suggesting that plasma CyPA is useful for the evaluation of the therapeutic effect by medication (n=45, P=0.038). Finally, event-free curve revealed that high plasma CyPA (>22 ng/ml) predicted poor outcome (death or lung transplantation, P<0.001).
Conclusions: CyPA is a Rho-kinase-dependent secreted protein that augments VSMC proliferation and progression of PH in humans.
- © 2012 by American Heart Association, Inc.