Cyclophilin A is a proinflammatory cytokine that activates endothelial cells

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 IkappaB-alpha phosphorylation and NF- kappaB 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-alpha. 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.