Skurk, T. & Hauner, H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int. J. Obes. Relat. Metab. Disord. 28, 1357-1364

Technische Universität München, München, Bavaria, Germany
International Journal of Obesity (Impact Factor: 5). 12/2004; 28(11):1357-64. DOI: 10.1038/sj.ijo.0802778
Source: PubMed


Obesity is the central promoter of the metabolic syndrome which also includes disturbed fibrinolysis in addition to hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes mellitus. Plasminogen activator inhibitor-1 (PAI-1) is the most important endogenous inhibitor of tissue plasminogen activator and uro-plasminogen activator, and is a main determinant of fibrinolytic activity. There is now compelling evidence that obesity and, in particular, an abdominal type of body fat distribution are associated with elevated PAI-1 antigen and activity levels. Recent studies established that PAI-1 is expressed in adipose tissue. The greater the fat cell size and the adipose tissue mass, the greater is the contribution of adipose production to circulating PAI-1. Experimental data show that visceral adipose tissue has a higher capacity to produce PAI-1 than subcutaneous adipose tissue. Studies in human adipocytes indicate that PAI-1 synthesis is upregulated by insulin, glucocorticoids, angiotensin II, some fatty acids and, most potently, by cytokines such as tumour necrosis factor-alpha and transforming growth factor-beta, whereas catecholamines reduce PAI-1 production. Interestingly, pharmacological agents such as thiazolidinediones, metformin and AT(1)-receptor antagonists were found to reduce adipose expression of PAI-1. In addition, weight loss by dietary restriction or comprehensive lifestyle modification is effective in lowering PAI-1 plasma levels. In conclusion, impaired fibrinolysis in obesity is probably also due to an increased expression of PAI-1 in adipose tissue. An altered function of the endocrine system and an impaired auto-/paracrine function at the fat cell levels may mediate this disturbance of the fibrinolytic system and thereby increase the risk for cardiovascular disease..

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    • "MCP-1 expression is increased in the adipose tissue of obese individuals and the overexpression of MCP-1 in murine adipose tissue leads to macrophage recruitment and insulin resistance (Kanda et al., 2006; Tateya, Tamori, Kawaguchi, Kanda, & Kasuga, 2010). The increase in the secretion of MCP-1 and PAI-1 has an ominous impact on the progression of atherogenesis (Aiello et al., 1999; Skurk & Hauner, 2004). As an early instigator of obesity-associated metabolic syndrome , increased oxidative stress and pro-inflammatory cytokine production in accumulated fat should be an important target for the development of new therapies. "
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    • "As a consequence, clots/matrices in chronic wounds obtain an altered composition and structure, as compared to those in acute wounds [47], [48], no longer support re-epithelialisation and granulation tissue formation, and therefore have to be removed. However, elevated levels of pro-inflammatory mediators, like TNF-α and C5a, in chronic wounds may lead to enhanced production of the fibrinolysis inhibitor PAI-1 [49], [50] as is reported for obese and diabetic patients [26], [27]. PAI-1 binds to and inactivates uPA and tPA which results in impaired lysis of clots and fibrin cuffs [26], [51]. "
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    ABSTRACT: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As haemostatic processes play an important role in wound healing, this study focused on the effects of maggot secretions on coagulation and fibrinolysis. The results showed that maggot secretions enhance plasminogen activator-induced formation of plasmin and fibrinolysis in a dose- and time-dependent manner. By contrast, coagulation was not affected by secretions. Biochemical studies indicated that a novel serine protease within secretions, designated Sericase, cleaved plasminogen to several fragments. Recombinant Sericase degraded plasminogen leading amongst others to the formation of the mini-plasminogen like fragment Val454-plasminogen. In addition, the presence of a non-proteolytic cofactor in secretions was discovered, which plays a role in the enhancement of plasminogen activator-induced fibrinolysis by Sericase. We conclude from our in vitro studies that the novel serine protease Sericase, with the aid of a non-proteolytic cofactor, enhances plasminogen activator-induced fibrinolysis.
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