Abstract 10569: Cyclophilin A Plays an Important Role in the Pathogenesis of Pulmonary Arterial Hypertension in Humans - Involvement of Rho-Kinase Pathway
Background: Pulmonary arterial hypertension (PAH) is associated with hypoxic exposure, enhanced 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. However, the role of CyPA in the pathogenesis of PAH in humans remains to be examined. In this study, we tested our hypothesis that CyPA contributes to pulmonary vascular remodeling in PAH patients.
Methods and Results: We used lung tissue and pulmonary artery VSMC from 8 PAH patients who underwent lung transplantation and 6 controls (normal tissue from lung cancer patients). Immunostaining of the lung revealed that CyPA expression in pulmonary VSMC was greater in the PAH patients compared with the controls. The number of CD45+ inflammatory cells in the lung and cell proliferation measured by PCNA+ cells were significantly increased in the PAH patients compared with the controls (both P<0.01). Organ culture experiments showed that CyPA secretion from the lung was significantly increased in the PAH patients compared with the controls (P<0.01). In cultured human pulmonary arterial VSMC, hypoxia (1% O2, 24 hours) significantly increased CyPA secretion and Rho-kinase activity compared with normoxic condition (21% O2, 24 hours). The extent of the hypoxia-induced CyPA secretion was significantly enhanced in PAH VSMC compared with control VSMC (P<0.0001), which was significantly inhibited by pretreatment with a specific Rho-kinase inhibitor, hydroxyfasudil (P<0.001). In contrast, treatment with human recombinant CyPA significantly increased Rho-kinase activity in PAH VSMC (P<0.01). Finally, serum levels of CyPA in patients with PAH (n=96) was significantly increased compared with the healthy controls (n=22) (16.5 ± 8.0 vs. 7.9 ± 5.1, P<0.0001). The serum levels of CyPA were significantly elevated in patients with advanced PA pressure (> 25 mmHg, n=73) compared with patients with lower PA pressure (< 20 mmHg, n=16) (P<0.001).
Conclusions: CyPA is a Rho-kinase-dependent secreted protein that augments VSMC proliferation and progression of PAH in humans.
- © 2011 by American Heart Association, Inc.