Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1

Abstract

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-a and transforming growth factor-b, 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.

The determinants of plasma plasminogen activator inhibitor-1 levels differ for American and Japanese men aged 40–49

“…Subsequently when we conducted a multiple regression analysis on Japanese subjects whose BMIs were greater than 25 kg/m 2 , we observed a marginal association of insulin with PAI-1 levels (data not shown). Studies in human adipocyte indicate that PAI-1 synthesis is upregulated by insulin 28 but the upregulation of PAI-1 synthesis by insulin may be evident only in obese subjects.…”

“…Second, there may be the differences in the fat cell size between these two ethnic groups. Americans may have smaller fat cells 28 than the Japanese as smaller fat cells produce less PAI-1 compared to larger fat cells [30][31][32] . Third, it may be explained by the differences in genetic factors between these ethnic groups.…”

Human visceral adipose tissue and the plasminogen activator inhibitor type 1

“…1,2 Increased PAI-1 levels are responsible for the impaired fibrinolysis that accompanies obesity and presumably contribute to increased cardiovascular risk in overweight and obese individuals. 3 Moreover, the apparent association between PAI-1 plasma levels, and insulin resistance 4 and incident type 2 diabetes mellitus 5 characterizes PAI-1 as a biological marker of the metabolic risk that accompanies (visceral) obesity.…”

“…Despite a large body of epidemiological and experimental evidence in support of a direct link between (visceral) adipose tissue and plasma PAI-1 levels, 1,2,6 clinical evidence is less obvious and the molecular basis for the association between (visceral) adipose tissue and plasma PAI-1 levels in man is still unclear. 7 The most obvious explanation for the association between plasma PAI-1 levels and visceral adipose tissue is a direct link in which the elevated plasma PAI-1 levels in (visceral) obesity result from PAI-1 release from (visceral) fat mass.…”

Hepatocyte growth factor secreted by cultured adipocytes promotes tube formation of vascular endothelial cells in vitro

“…Adipose tissue is now recognized as an endocrine organ that secretes many cytokines and growth factors. 4,5 For example, several reports have demonstrated that adipocytes secrete tumor necrosis factor alpha, 6 resistin, 7 plasminogen activator inhibitor-1 (PAI-1), 8 leptin 9 and angiotensinogen. 10,11 Vascular endothelial growth factor (VEGF) is an angiogenetic growth factor, which is secreted by rat adipose tissue ex vivo.…”