ELEVATIONS OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND DIFFERENTIAL EXPRESSION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR IN DISEASED AORTA

Purpose: Elevations of plasmin have been implicated in the pathogenesi s of abdominal aortic aneurysms (AAA) because of its ability to digest extracellular matrix proteins. Plasminogen activators regulate the co nversion of plasminogen to plasmin. Tissue-type plasminogen activator (tPA) is more important in modulation of fibrinolysis, and urokinase-t ype plasminogen activator (uPA) is predominant in tissue remodeling. T he purpose of this study was to determine the levels of plasminogen ac tivators in diseased aorta because they may be responsible for the inc reased plasmin levels previously described in AAA. Methods: Levels of tPA and uPA in AAA, occlusive, and normal (organ donor) aorta were stu died in tissue explant supernatants. Supernatant tPA and uPA levels we re measured with an enzyme-linked immunosorbent assay. Northern analys is was used to quantitate uPA messenger RNA (mRNA) levels in aortic ti ssue. Results: Levels of tPA in the supernatants were similar in occlu sive (20+/-4 ng/ml) and AAA (23+/-8) aorta, but threefold higher than in normal aorta (7+/-5; p <0.005 for normal vs occlusive and p <0.001 for normal vs AAA). In contrast, uPA supernatant levels were different ially expressed, with the highest level existing in AAA (9.7+/-2.7 ng/ ml), followed by occlusive (4.9+/-3.5), and the lowest levels in norma l aorta (1.2+/-0.7 p <0.05 for normal vs occlusive, p <0.001 for norma l vs AAA, and p <0.005 for occlusive vs AAA). Inhibition of protein or RNA synthesis by addition of cyclohexamide or actinomycin D, respecti vely, revealed no significant difference between treated and control s upernatants, suggesting that the increases were caused by protein rele ase rather than active synthesis. Levels of uPA mRNA followed the same trend as the supernatant uPA levels (AAA 1.07+/-0.54, occlusive 0.54/-0.08, and normal aorta 0.01+/-0.01). Conclusions: Levels of tPA were similar in aneurysmal and occlusive aorta, but exhibited a threefold increase over normal aorta, suggesting that the elevations of tPA are associated with the arteriosclerosis present in both aneurysmal and oc clusive disease. Differences in uPA levels were significant between al l three groups, with the highest levels in AAA and the lowest levels i n normal specimens. Northern analysis of uPA mRNA followed the same tr end, suggesting that the increase in uPA may be regulated at the level of transcription. As uPA plays an important role in tissue remodeling , our findings may also reflect the relative tissue repair activities in these three types of specimens and may explain the previously repor ted increased levels of plasmin seen in AAA.