Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity.
Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in vivo. Circulating PAI-1 levels are elevated in patients with coronary heart disease and may play an important role in the development of atherothrombosis by decreasing fibrin degradation. Increased PAI-1 expression can also directly influence vessel wall remodelling. Prospective cohort studies have underlined the association between increased plasma PAI-1 levels and the risk of coronary events, but the predictive capacity of PAI-1 disappeared after adjustments for insulin resistance markers. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. Recently, production of PAI-1 by adipose tissue, in particular by fat from omentum, has been evidenced, and it has been proposed that it could be responsible for the elevated plasma PAI-1 level observed in insulin resistance. The role of stroma cells, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta as possible enhancers of PAI-1 synthesis are presently emphasized. Glucocorticoids and insulin may also be implicated. Moreover, a weak genetic control of plasma PAI-1 concentration has been described in patients with high plasma levels of PAI-1. The role of PAI-1 in the development of adipose tissue metabolism is important to consider as PAI-1 -/- mice submitted to a high-fat diet showed changes in cell composition of adipose tissue and in plasma insulin and triglyceride levels.
Juhan-Vague
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I
Laboratory of Hematology, Faculty of Medicine, CHU Timone, Marseille, France. ijuhan@mail.ap-hm.fr
Alessi
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MC
Morange
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PE
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002318:Cardiovascular Diseases / Q000503:physiopathology; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance; D009765:Obesity / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D011110:Polymorphism, Genetic; D013927:Thrombosis / Q000503:physiopathology*
D017395:Plasminogen Activator Inhibitor 1