Cyclophilin A–FoxO1 signaling pathway in endothelial cell apoptosis

Abstract

Cyclophilin A (CyPA), which is encoded by PPIA, is a ubiquitously expressed intracellular protein and is secreted in response to inflammatory stimuli. CyPA stimulates proinflammatory signaling pathways in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), promotes VSMC migration and proliferation, EC adhesion molecules expression, and inflammatory cell chemotaxis and apoptosis. Moreover, CyPA activates mitogen-activated protein kinases, including ERK1/2, JNK, and p38, and stimulates IkB-α phosphorylation, NF-kB activation, and vascular cell adhesion molecule-1 and E-selectin expression in human umbilical vein ECs. Therefore, we hypothesized that CyPA regulated transcription factor FoxO1 phosphorylation and transcriptional activity and the expression of downstream genes involved in vascular EC activation, thus activated vascular ECs in vitro. We found that intracellular CyPA promoted FoxO1 dephosphorylation at Ser256, nuclear accumulation, and transcriptional activity by interacting with it. Moreover, CyPA induced FoxO1-dependent expression of downstream genes involved in EC chemotaxis and apoptosis, including monocyte chemoattractant protein-1 and BCL-2-interacting mediator of cell death, and stimulated the apoptosis of human umbilical vein ECs in vitro.