Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries.

Abstract

High plasma levels of plasminogen activator inhibitor type-1 (PAI-1), the principal inhibitor of the fibrinolytic system, have been associated with thrombotic and arterial disease. To study PAI-1 expression in healthy and atherosclerotic human arteries, a detailed analysis was made by light and electron microscopy immunocytochemistry and by in situ hybridization. In healthy arteries PAI-1 was found both at the level of endothelial cells and of smooth muscle cells (SMCs) of the arterial media. In early atherosclerotic lesions PAI-1 was also detected in intimal SMCs and in extracellular areas in association with vitronectin. Immunogold analysis by electron microscopy revealed PAI-1 in vesicular structures in endothelial cells and in SMCs with normal or foam cell characteristics. In advanced atheromatous plaques, PAI-1 mRNA expression in SMCs within the fibrous cap was increased compared with SMCs located in the adjacent media or in normal arterial tissue. PAI-1 mRNA was also detected in macrophages located at the periphery of the necrotic core. The increased synthesis of PAI-1 by cellular components of the atherosclerotic plaque and the extracellular accumulation of PAI-1 may contribute to the thrombotic complications associated with plaque rupture and possibly play a role in the accumulation of extracellular matrix deposits.

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…Previous studies reported the correlation of PAI‐1 with multiple conventional risk factors of CHD, eg, obesity, glycemic traits, and type 2 diabetes mellitus,6 metabolic syndrome,7 as well as correlation with vessel wall thickness 8. In addition, higher PAI‐1 expression was observed in coronary artery tissues in the presence of atherogenic lesions 9, 10. These findings raise interest in whether PAI‐1 plays a role in early atherosclerosis versus acute thrombosis.…”

Physical Activity Status and Adverse Age-Related Differences in Coagulation and Fibrinolytic Factors in Women

“…32 Elevated PAI-1 gene expression, localization, and production have been reported to occur in injured atherosclerotic arteries. 41 In contrast, elevated t-PA activity is associated with a decreased risk of cardiovascular events. 42 Thus, the absence of age-associated impairments in the fibrinolytic system in the physically active women may be mechanistically involved in the lower incidence of atherothrombotic events observed in this population.…”

Effective lysis of model thrombi by a t‐PA mutant (A473S) that is resistant to α2‐antiplasmin

“…In human aorta, local concentrations of a 2 -AP represented about 10±20% of the concentration found in normal circulating blood (1 mmol/l). In contrast, although plasminogen activators and their inhibitors were elevated in the vessel wall (Schneiderman et al, 1992;Lupu et al, 1993;Padro et al, 1995), they were present only in the nmol/l range (Robbie et al, 1996b). By virtue of its high local concentration and acting as an inhibitor of both plasmin and t-PA, a 2 -AP could have a profound impact on fibrin stability, potentially influencing local plasmin generation as well as plasmin activity.…”