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Role of fibrinolytic and anti-fibrinolytic agents

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  2. Role of fibrinolytic and anti-fibrinolytic agents
  3. References

Increased circulating levels of plasminogen activator inhibitor (PAI)-1 are associated with the metabolic syndrome and may contribute to the increased cardiovascular risk that characterizes this syndrome. Indeed, the main function of PAI-1 is to promote fibrin accumulation. However, PAI-1 is also involved in cell migration and adhesion, and in angiogenesis and fibrosis. This means PAI-1 is central to tissue remodeling, especially in atherosclerotic vessel walls and adipose tissue. PAI-1 is produced from adipose tissue, especially visceral fat. In addition, overproduction of PAI-1 has been found from the steatotic liver of obese individuals. PAI-1 is an acute-phase protein and a variety of data argue for a local coregulation of PAI-1 expression by the inflammatory environment (mainly tumor necrosis factor and transforming growth factor-β) and by the hormones insulin and cortisol [1,2]. Recent results suggest that increased oxidative stress in accumulated fat dysregulates production of several adipocytokines, among them PAI-1 [3].

It appears that PAI-1 may contribute to the development of obesity and the metabolic syndrome. An interaction of PAI-1 with the insulin response has been shown in vitro. Vitronectin, an abundant adhesive glycoprotein in plasma and extracellular matrix, binds PAI-1 and controls its activity by stabilizing PAI-1 in the active form. The binding of vitronectin to its receptor, integrin αvβ3, potentiates insulin's action by increasing expression of insulin receptor substrate (IRS-1) and phosphorylation of protein kinase B. The addition of PAI-1 reverses this effect and therefore inhibits transmission of the insulin signal [4].

In vivo evidence of a direct role of PAI-1 in obesity and insulin resistance has been provided in mice. Disruption of the PAI-1 gene in genetically obese ob/ob mice reduces adiposity and improves the metabolic profile [5]. The development of obesity and insulin resistance in wild-type mice on a high-fat diet was completely prevented in those mice lacking PAI-1. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro[6]. Interestingly, we found that transgenic mice overexpressing murine PAI-1 within adipose tissue and kept on a high-fat diet developed subcutaneous adipocyte hypotrophy with increased expression of preadipocyte factor-1, which blocks adipocyte differentiation [7]. Aged transgenic mice also present lower body weight and higher fasting insulin levels than wild type mice [8]. In vitro, active PAI-1 was able to inhibit preadipocyte attachment to vitronectin [9]. These results suggest that high levels of circulating and adipose tissue PAI-1 are able to modify the development of adipose tissue and insulin resistance. Recent data show that a pharmacological inhibitor of PAI-1 given to aged mice is associated with a small improvement in metabolic parameters [8]. This suggests that in vivo inhibition of PAI-1 could exert a beneficial effect.

Some clinical data also support a direct contribution of PAI-1 to the development of obesity and the metabolic syndrome. The prospective study IRAS [10] followed 1047 non-diabetic subjects in relation to incident diabetes within 5 years. The 144 subjects who presented with diabetes at follow-up had higher baseline levels of PAI-1. PAI-1 predicted the development of diabetes independently of biological features of the metabolic syndrome, C-reactive protein and other known risk factors for diabetes. It has recently been shown that −675 4G/4G PAI-1 genotype is associated with an increased risk of obesity [11], with higher blood concentrations of glucose, insulin, triglyceride and lower HDL-cholesterol [12]. This might suggest an increased insulin resistance in these carriers. Taken together, these results support an effect of PAI-1 on adiposity, insulin resistance and diabetes.

More investigations are required to unravel a possible contribution of PAI-1 to the development of the metabolic syndrome and to determine if PAI-1 could represent a potential target for therapeutic intervention aiming to decrease the risk of both cardiovascular disease and Type 2 diabetes.

References

  1. Top of page
  2. Role of fibrinolytic and anti-fibrinolytic agents
  3. References