QUANTIFICATION OF PLASMINOGEN ACTIVATORS AND THEIR INHIBITORS IN THE AORTIC VESSEL WALL IN RELATION TO THE PRESENCE AND SEVERITY OF ATHEROSCLEROTIC DISEASE

Increased expression of plasminogen activator inhibitor-1 (PAI-1) has been demonstrated in the human atherosclerotic vessel wall and may con tribute to the impaired plasma fibrinolytic capacity in patients at hi gh risk of atherothrombotic events. In addition, the mural PA/plasmin system may have important pathobiologic functions during atherogenesis . We quantitatively analyzed PAs of the tissue type (TPA) and urokinas e type (UPA), PAIs, and plasminogen in protein extracts from different layers of human aorta in relation to the presence and severity of ath erosclerotic lesions. In comparison with normal control vessels, intim al and neointimal TPA concentrations were reduced in atherosclerotic a ortas except in the necrotic core areas of advanced plaques, where TPA was mainly complexed to PAI-1 in extracellular matrix deposits. In th e media, TPA antigen was higher in lesional segments and closely assoc iated with smooth muscle cells. UPA antigen was increased in the intim a of atherosclerotic lesions and colocalized with tissue-infiltrating macrophages and neointimal smooth muscle cells. By spectrophotometric assay, neither TPA nor UPA activity could be detected in intimal or me dial extracts. PAI-1 concentrations increased significantly in the int ima of atherosclerotic segments compared with adjacent uninvolved area s or control aortas. The immunohistochemical distribution of PAI-1 was similar to that observed for TPA. A large excess of PAI-1 over PA con centrations, particularly in the intimal layer, characterizes atherosc lerotic lesions of the human aorta and suggests that PA action is loca lly confined and counterbalanced by enhanced PAI expression and accumu lation.