Abstract 681: Leptin Induction of Human Mononuclear Cell Tissue Factor
Obesity is a major modifiable risk factor for cardiovascular disease. Leptin, the hormone synthesized and released primarily by adipose tissue and found increased in obese individuals, has been implicated in the regulation of inflammation and arterial and venous thrombosis. Since expression of tissue factor (TF), the main trigger of coagulation in vivo, is abundant in the adipose tissue, we investigated whether leptin could modulate monocyte TF expression. To test this hypothesis, mononuclear leukocytes from healthy volunteers were incubated for 6 h with or without leptin at 37°C. At the end of incubation, cells were disrupted and tested for procoagulant activity and antigen levels by a one-stage clotting assay and by ELISA, respectively. Our results demonstrate that leptin induced TF activity and antigen in a dose-dependent fashion. Leptin exerted its effect at the transcription level, since reverse transcriptase PCR indicated development of TF mRNA in monocytes. The mechanism by which leptin induced TF synthesis resides in an increased migration of the transacting factor c-Rel/p65 into the nucleus, as determined by electromobility shift assay. Preincubation with mitogen-activated protein kinase (MAPK) inhibitors indicated the involvement of a p38 MAPK signalling, not of the ERK1/2 pathway, which is known to be implicated in endotoxin-mediated TF expression. In a selected sample of obese patients, loss of body weight by dietary modification led to decreased circulating leptin levels, accompanied by a reduction in plasma TF as well as in TF expression in resting and endotoxin-stimulated mononuclear cells. Thus, we have reported here the original observation that leptin can induce TF expression by human mononuclear cells, suggesting an additional role for this hormone in the cardiovascular risk associated with obesity.