CHANGES IN ARTERIAL EXPRESSION OF FIBRINOLYTIC SYSTEM PROTEINS IN ATHEROGENESIS

Plasminogen activators (PAs) and their inhibitor, plasminogen activato r inhibitor type-1 (PAI-1), have been implicated in modulation of lumi nal fibrinolysis and mural proteolysis contributing to atherogenesis. Expression of PAs/PAI-1 (normalized to extracted tissue protein) was d elineated by assays of conditioned media and of extracts from walls of human arterial segments in culture. Arterial specimens (n = 39 from 2 6 subjects) were divided into four groups: normal (n = 14), fatty stre ak (n = 6), moderate atherosclerosis (mural thickening with <70% lumen obstruction, n = 5), and severe atherosclerosis (mural thickening wit h >70% lumen obstruction, n = 14). Paired samples from the same indivi dual comprising a normal arterial segment and an atherosclerotic segme nt were evaluated also. A fourfold molar excess in PAI-1:t-PA was seen in conditioned media from samples with any evidence of atherosclerosi s compared with normal specimens (normal 21 +/- 4, diseased 82 +/- 21, P less than or equal to .05). Compared with normal pairs, the tissue content of PAI-1 (ng) was increased in fatty streak lesions (n = 3, no rmal 35 +/- 12, fatty streak 50 +/- 8, P less than or equal to .05); s table to decreased in moderate atherosclerosis (n = 3, normal 34 +/- 3 , moderate 22 +/- 7, P = .16); and increased in severe atherosclerosis (n = 6, normal 48 +/- 9, severe 85 +/- 19, P less than or equal to .0 5). The tissue content of PAs (ng), though not increased in fatty stre ak lesions, was elevated in moderately and severely atherosclerotic se gments (normal 0.7 +/- 0.2, moderate 1.6 +/- 0.1; normal 0.8 +/- 0.3, severe 2.1 +/- 0.3, P less than or equal to 0.05 for each comparison). Atherogenesis is associated with decreased luminal fibrinolytic capac ity that may exacerbate thrombosis. Decreased mural proteolysis in ear ly atherogenesis may exacerbate matrix accumulation. Increased mural p roteolysis later is associated with, and may potentiate, smooth muscle cell migration and proliferation.