Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity

Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhi bitor of plasminogen activation in vivo. Circulating PAI-1 levels are eleva ted in patients with coronary heart disease and may play an important role in the development of atherothrombosis by decreasing fibrin degradation. In creased PAI-1 expression can also directly influence vessel wall remodellin g. Prospective cohort studies have underlined the association between incre ased plasma PAI-1 levels and the risk of coronary events, but the predictiv e capacity of PAI-1 disappeared after adjustments for insulin resistance ma rkers. The insulin resistance syndrome, which is characterized partly by ob esity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. Recently, production of PAI-1 by adipose tissue, in part icular by fat from omentum, has been evidenced, and it has been proposed th at 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 PA I-1 synthesis are presently emphasized. Glucocorticoids and insulin may als o be implicated. Moreover, a weak genetic control of plasma PAI-1 concentra tion has been described in patients with high plasma levels of PAI-1. The r ole of PAI-1 in the development of adipose tissue metabolism is important t o 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.