Plasminogen Activator Inhibitor1

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Although PAI-1 is primarily derived from platelets and the endothelium, it has been demonstrated that most of the elevated concentrations of this regulatory protein of the coagulation cascade in inflammatory and obese states is attributable to an upregulated expression by adipose tissue itself (12,58). Therefore, WAT represents a quantitatively relevant source of PAI-1 production, with consequently increased circulating concentrations present in obesity. Stromal cells have been shown to be the main PAI-1 producing cells in human fat, with a fivefold higher expression in the visceral than in the subcutaneous depots, which is in agreement with the strong relationship observed between circulating PAI-1 concentrations and visceral fat accumulation (59). However, whether adipose tissue itself directly contributes to circulating PAI-1, or whether it exerts an indirect effect via adipokines, such as TNF-a , IL-1^, and TGF-^, to stimulate PAI-1 production by other cells has not been clearly established. Moreover, PAI-1 gene expression is increased by hyperglycemia, insulin, glucocorticoids, angiotensin II, thrombin, and LDL cholesterol, whereas IL-6, estrogens, and ^-adrenoceptor agonists exert an inhibitory effect (8). PAI-1 activity has been shown to play a key role in thrombus formation upon unstable atherosclerotic plaque rupture through the inhibition of fibrin clot breakdown. In addition, by altering the fibrinolytic balance, PAI-1 also contributes to vascular structure remodeling. A close correlation between plasma PAI-1 with visceral adiposity and increased myocardial infarct was established a decade ago (7). In fact, in humans plasma PAI-1 concentrations correlate with atherosclerotic events and mortality, with some studies suggesting that PAI-1 may be an independent risk factor for coronary artery disease. In this respect, increased plasma PAI-1 concentrations have been observed in obese patients and a close correlation with an abdominal pattern of adipose tissue distribution in both men and women, as well as a positive association with other components of the insulin resistance syndrome, have been reported (7,59).

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