The urokinase system in the pathogenesis of atherosclerosis

Atherogenesis refers to the development of atheromatous plaques in the inner lining of the arteries. These atherosclerotic lesions are characterized by accumulation of monocyte-derived macrophage-foam cells loaded with cholesterol, which eventually undergo apoptotic death, leading finally to formation of the necrotic core of the plaque. Atheroma formation also involves the recruitment of smooth muscle cells (SMC) from the media into the intima, where they proliferate and form the neointima in a process called “remodeling”. Cells in the advanced atherosclerotic plaques express high levels of the serine protease urokinase-type plasminogen activator (uPA) and its receptor (uPAR). uPA is a multi-functional multi-domain protein that is not only a regulator of fibrinolysis, but it is also associated with several acute and chronic pathologic conditions. uPA mediate the extracellular matrix (ECM) degradation, and plays a pivotal role in cell adhesion, migration and proliferation, during tissue remodeling. On cell surface uPA binds to the high affinity urokinase receptor, providing a strictly localized proteolysis of ECM proteins. The uPA/uPAR complex also activates intracellular signaling, thus regulating cellular function. An imbalance in the uPA/uPAR system leads to dis-orders in tissue structure and function. This review summarizes recent progress in understanding the role and mechanisms of the uPA/uPAR system in atherogenesis.