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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1186.)
© 2004 American Heart Association, Inc.

Vascular Biology

Cyclophilin A Is a Proinflammatory Cytokine that Activates Endothelial Cells

Zheng-Gen Jin; Andreea O. Lungu; Liang Xie; Meng Wang; Chelsea Wong; Bradford C. Berk

From the Department of Medicine and Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Sciences, Rochester, NY.

Correspondence to Dr Zheng-Gen Jin, University of Rochester, Center for Cardiovascular Research, 601 Elmwood Avenue, Box 679, Rochester NY 14642. E-mail zheng-gen_jin{at}urmc.rochester.edu

Objective— Cyclophilin A (CyPA) is an abundant intracellular protein that is considered to be the main target of the immunosuppressive drug cyclosporine A. We and others showed that CyPA is secreted from smooth muscle cells and macrophages in response to oxidative stress and lipopolysaccharide, suggesting a role for CyPA in inflammation. We therefore studied the proinflammatory effects of CyPA on vascular endothelium.

Methods and Results— Because atherosclerosis is an inflammatory disease, we studied expression of CyPA in atherosclerotic plaques from the ApoE–/– mouse. Using immunohistochemistry, we showed that CyPA was highly expressed in these plaques. Because endothelial cells (EC) are important mediators of inflammation, we next studied the ability of CyPA to activate EC. Human recombinant CyPA activated mitogen-activated protein kinases, including ERK1/2, JNK, and p38 in cultured human umbilical vein EC. CyPA also stimulated IB- phosphorylation and NF-B activation, and induced expression of adhesion molecules including E-selectin and vascular cell adhesion molecule-1. Furthermore, the combination of CyPA and cycloheximide induced EC apoptosis similar to the proapoptotic effect of tumor necrosis factor-.

Conclusions— Our data indicate that CyPA has proinflammatory effects on EC and may play an important role in the pathogenesis of inflammatory diseases, such as atherosclerosis.

This work defines a new role of cyclophilin A (CyPA) in endothelial cells as pro-inflammatory cytokine. We showed that CyPA was highly expressed in atherosclerotic plaques, and CyPA stimulated endothelial activation, induced expression of adhesion molecules and induced apoptosis, suggesting a potential role of CyPA in the pathogenesis of atherosclerosis.

Key Words: cyclophilin A • mitogen-activated protein kinases • adhesion molecules • endothelial cell • atherosclerosis

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