• oxidative stress
• heat shock proteins
• cyclophilin A
• vascular smooth muscle
• signal transduction
• atherosclerosis

• Ang II, angiotensin II
• CyPA, cyclophilin A
• ERK, extracellular regulated signal kinase
• HSP90, heat shock protein 90
• PDGF, platelet derived growth factor
• PPIase, peptidyl-prolyl cis-trans isomerase
• ROS, reactive oxygen species
• SOXF, secreted oxidative stress induced factors
• VSMC, vascular smooth muscle cells

Oxidative stress and the production of intracellular reactive oxygen species (ROS), such as superoxide (O₂^.−), hydrogen peroxide (H₂O₂), and hydroxyl radical (OH^.), have been implicated in the pathogenesis of cardiovascular disease, in part by promoting vascular smooth muscle proliferation.^1–4 Within the vessel wall, ROS are generated by several mechanisms, including vascular NAD(P)H oxidases.^5,6 ROS formation can be stimulated by mechanical stress, environmental factors, platelet derived growth factor (PDGF), angiotensin II (Ang II), and low density lipoproteins.^7–9 Because many risk factors for coronary artery disease such as hyperlipidaemia, hypertension, diabetes, and smoking increase production of ROS, it has been suggested that changes in vessel redox state are a common pathway involved in the pathogenesis of atherosclerosis and vascular injury.^1,6,10

Several key findings support the concept that ROS contribute to vascular diseases through effects on vascular smooth muscle cells (VSMC). Initial studies in our laboratory demonstrated that ROS stimulate cultured VSMC proliferation and activate intracellular kinases such as mitogen activated protein kinases (MAPK) which are associated with proto-oncogene expression and cell growth.^4,11,12 Furthermore, we observed that in the injured vessel wall there is increased ROS production. Antioxidants decrease neointimal VSMC proliferation and promote outward vessel remodelling in the pig coronary injury model.^13,14 We showed that many proteins kinases are involved in ROS mediated signalling and gene expression.^4,15–18 Recently we have demonstrated the novel finding that ROS stimulated VSMC synthesise and secrete proteins which may activate intracellular events in an autocrine and paracrine fashion.^19,20 In this article, we describe these factors, termed SOXF, for Secreted OXidative stress …