Signaling mechanisms for oxidized LDL-induced oxidative stress and the upregulation of plasminogen activator inhibitor-1 in vascular cells

An elevated level of oxidized LDL (ox-LDL) plays a crucial role in the development of atherosclerotic cardiovascular disease. LDL may be oxidized by reactive oxygen species in vivo. Ox-LDL stimulates the generation of reactive oxygen species through NADPH oxidase, increases oxidative stress and promotes foam cell formation by receptor-mediated uptake of ox-LDL. Ox-LDL is a potent agonist for the expression of multiple mediators involved in atherothrombosis. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of plasminogen activators, is one of the inducible mediators implicated in both thrombogenesis and atherogenesis. Increased levels of PAI-1 were detected in patients with atherosclerosis or diabetic cardiovascular complications. Heat shock factor-1 (HSF1) is the key mediator for stress response-related proteins. Our recent studies demonstrated that HSF1 is implicated in ox-LDL-induced upregulation of PAI-1 gene in vascular endothelial cells. Lectin-like ox-LDL receptor-1, NADPH oxidase, H-Ras, protein kinase C-beta and Raf-1/ERK1/2 pathway are involved in ox-LDL-induced HSF1 and PAI-1 upregulation in endothelial cells. ox-LDL-induced PAI-1 production in vascular endothelial cells is one of the cellular responses to oxidative stress that contribute to atherogenesis and thrombosis.