Department of Cardiology and Pulmonary Medicine, University of Goettingen, Robert Koch Strasse 40, D-37075 Goettingen, Germany.
Curr Pharm Des. 2014;20(4):635-40. doi: 10.2174/13816128113199990021.
Epidemiological evidence strongly links excess body weight with an increased risk to develop atherothrombotic complications. Obesity is frequently associated with systemic and local inflammation as well as elevated circulating leptin levels, and clinical studies found hyperleptinemia to correlate not only with measures of adiposity, but also with circulating biomarkers of an increased metabolic and cardiovascular risk or surrogate markers of subclinical atherosclerosis. Moreover, experimental studies in mice with systemic disruption of the leptin-leptin receptor system as well as after administration or neutralization of the adipokine demonstrated that leptin promotes both arterial and venous thrombosis. In addition to directly binding to and activating platelets and thus potentiating their aggregation in response to agonist stimulation, leptin enhances the expression of prothrombotic and anti-fibrinolytic proteins in vascular and inflammatory cells. On the other hand, its ability to mobilize and recruit vascular progenitor cells from the bone marrow to sites of vascular injury was found to be impaired in hyperleptinemic, obese humans and rodents. Thus, leptin promotes thrombus formation and resolution by several different mechanisms involving primary hemostasis, the coagulation cascade as well as the integrity of the vessel wall. Dissection of the molecular mechanisms underlying each of its actions may pave the road for novel therapeutic options in targeting the increased risk of thrombosis associated with obesity, keeping in mind unresolved issues of a cell-specific leptin resistance as well as individual differences in the responsiveness to leptin.
流行病学证据强烈表明，超重与动脉血栓形成并发症的风险增加有关。肥胖常伴有全身和局部炎症以及循环瘦素水平升高，临床研究发现高瘦素血症不仅与肥胖程度的测量值相关，还与代谢和心血管风险的循环生物标志物或亚临床动脉粥样硬化的替代标志物相关。此外，对全身性破坏瘦素-瘦素受体系统的小鼠以及给予或中和脂肪细胞因子后的实验研究表明，瘦素可促进动脉和静脉血栓形成。除了直接结合并激活血小板，从而增强其在激动剂刺激下的聚集外，瘦素还可增强血管和炎症细胞中促血栓形成和抗纤维蛋白溶解蛋白的表达。另一方面，在高瘦素血症、肥胖的人类和啮齿动物中发现，其动员和招募骨髓中的血管祖细胞到血管损伤部位的能力受损。因此，瘦素通过涉及初级止血、凝血级联和血管壁完整性的几种不同机制促进血栓形成和溶解。解析其每种作用的分子机制可能为针对肥胖相关血栓形成风险增加的新型治疗方法铺平道路，但需牢记细胞特异性瘦素抵抗以及对瘦素反应的个体差异等尚未解决的问题。
