Napoleone E, DI Santo A, Amore C, Baccante G, di Febbo C, Porreca E, de Gaetano G, Donati M B, Lorenzet R
Centro Giovanni Paolo II di Ricerche e Formazione ad Alta Tecnologia nelle Scienze Biomediche, Università Cattolica, Campobasso, Italy.
J Thromb Haemost. 2007 Jul;5(7):1462-8. doi: 10.1111/j.1538-7836.2007.02578.x. Epub 2007 Apr 9.
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.
To investigate the role of tissue factor (TF), the pivotal agonist of the clotting cascade, as a link between obesity and cardiovascular disease.
In 15 obese patients, plasma levels of leptin and TF as well as TF expression in resting and endotoxin-stimulated mononuclear leukocytes (MN) were increased when compared with healthy donors. In a selected sample of obese patients, loss of body weight led to decreased circulating leptin levels, accompanied by a reduction in plasma TF as well as in TF expression, both in resting and endotoxin-stimulated MN. In subsequent in vitro experiments, leptin was incubated with MN from healthy subjects. Leptin induced TF activity and antigen in a dose-dependent fashion, as assessed by clotting assay and ELISA, respectively. Increased migration of c-Rel/p65 into the nucleus, as determined by EMSA, and development of TF mRNA in monocytes, as assessed by RT-PCR, were observed. Experiments with mitogen-activated protein kinase (MAPK) inhibitors, indicated the involvement of p38 and ERK1/2 pathways.
The presence of TF-expressing MN in blood from obese subjects and the in vitro induction of TF by pharmacologic concentrations of leptin in MN from healthy subjects suggest that TF expression by leptin-stimulated monocytes may contribute to the cardiovascular risk associated with obesity.
肥胖是心血管疾病的主要可改变风险因素。瘦素是主要由脂肪组织合成和释放的激素，在肥胖个体中含量升高，与炎症调节以及动静脉血栓形成有关。
研究凝血级联反应的关键激活剂组织因子（TF）作为肥胖与心血管疾病之间联系的作用。
与健康供体相比，15例肥胖患者血浆中的瘦素和TF水平以及静息和内毒素刺激的单核白细胞（MN）中的TF表达均升高。在一组选定的肥胖患者样本中，体重减轻导致循环瘦素水平降低，同时血浆TF水平以及静息和内毒素刺激的MN中的TF表达均降低。在随后的体外实验中，将瘦素与健康受试者的MN一起孵育。分别通过凝血试验和ELISA评估，瘦素以剂量依赖的方式诱导TF活性和抗原。通过电泳迁移率变动分析（EMSA）测定，观察到c-Rel/p65向细胞核的迁移增加，通过逆转录-聚合酶链反应（RT-PCR）评估，单核细胞中TF mRNA增加。用丝裂原活化蛋白激酶（MAPK）抑制剂进行的实验表明p38和ERK1/2途径参与其中。
肥胖受试者血液中存在表达TF的MN，以及健康受试者的MN中药物浓度的瘦素在体外诱导TF，提示瘦素刺激的单核细胞表达TF可能导致与肥胖相关的心血管风险。
