COMPARATIVE-ANALYSIS OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 EXPRESSION IN DIFFERENT TYPES OF ATHEROSCLEROTIC LESIONS IN CORONARY-ARTERIES FROM HUMAN HEART EXPLANTS

Objectives: Clinical manifestations of coronary heart disease result p rimarily from the progressive development of atherosclerotic plaques a nd subsequent thrombus formation; processes which may be accelerated b y an enhanced expression of plasminogen activator inhibitor (PAI-1) in the vessel wall. In the present study, content and expression of PAI- 1 were comparatively analyzed in human coronary arteries in relation t o the presence and severity of atherosclerotic lesions. Methods: Segme nts of coronary arteries obtained from heart explants (n = 15) were cl assified by the presence and types of atherosclerotic lesions. Antigen and activity levels of PAI-1 were determined in protein extracts of i ntimal and medial layers. In situ hybridization and immunohistochemica l analyses were performed on serial sections of representative tissue specimens. Results: Total PAI-1 antigen consistently increased from ma croscopically normal areas (MNAs) to early lesions (ELs) and to maxima l levels in fibrous (FPs) and calcified (CPs) plaques, No PAI activity was detected, although PAI-1 in its free form was present in ail vasc ular specimens. Both free PAI-1 and PAI-1 complexed with plasminogen a ctivators were significantly increased in extracts of advanced lesions . However, there was a 2-3 fold molar excess of free versus complexed PAI-1 in FPs and CPs. These findings suggest the presence of relevant amounts of PAI-1 in its substrate rather than in its inhibitor conform ation in areas of advanced lesions. Compared with MNAs, PAI-1 mRNA was strongly expressed within the thickened intima of ELs. The highest PA I-1 expression was observed in FPs and CPs, being mainly localized in areas surrounding the necrotic cores in co-localization with infiltrat ing macrophages. Conclusions: PAI-1 content is consistently increased in relation to the severity of the lesions in atherosclerotic coronary arteries. The concomitant elevation of PAI-1 mRNA suggests that the P AI-1 increase is regulated by local synthesis in the areas of atherosc lerotic lesions. (C) 1997 Elsevier Science B.V.