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.