Cyclophilin A is a secreted growth factor induced by oxidative stress

Reactive oxygen species have been implicated in the pathogenesis of atheros clerosis, hypertension, and restenosis, in part by promoting vascular smoot h muscle cell (VSMC) growth. Many VSMC growth factors are secreted by VSMC and act in an autocrine manner. Here we demonstrate that cyclophilin A (CyP A), a member of the immunophilin family, is secreted by VSMCs in response t o oxidative stress and mediates extracellular signal-regulated kinase (ERK1 /2) activation and VSMC growth by reactive oxygen species. Human recombinan t CyPA can mimic the effects of secreted CyPA to stimulate ERK1/2 and cell growth. The peptidyl-prolyl isomerase activity is required for ERK1/2 activ ation by CyPA, In vivo, CyPA expression and secretion are increased by oxid ative stress and vascular injury. These findings are the first to identify CyPA as a secreted redox-sensitive mediator, establish CyPA as a VSMC growt h factor, and suggest an important role for CyPA and enzymes with peptidyl- prolyl isomerase activity in the pathogenesis of vascular diseases.