Leptin in Vascular Disease

肥胖在美国很流行，并且正在成为一个强大的独立危险因素 用于动脉粥样硬化性血管疾病的并发症，如心肌梗死和中风。 由于动脉粥样硬化斑块上的血栓形成是心肌梗死的直接原因， 在脑梗死和中风中，肥胖状态可能促进脑梗死部位血栓形成的发展。 血管疾病瘦素是一种由脂肪细胞产生的激素，随着肥胖而增加， 是导致肥胖相关心血管风险增加的介质之一。 我们最近已经证明，瘦素或瘦素受体缺乏是保护， 在动脉损伤的小鼠模型中的血栓形成。此外，瘦素的这种保护作用 用瘦素替代来逆转血栓形成的不足。符合血栓前病变 瘦素在人体中的作用，最近的临床试验表明，血浆瘦素升高是心血管事件的独立危险因素。 该提案的目标是描述不同水平的ieptin对 血栓形成和动脉粥样硬化。此外，将使用Cre-loxP系统产生具有血小板和内皮瘦素受体缺陷的小鼠，以确定参与介导瘦素的不良血管作用的相关靶组织。 这些研究将确定瘦素和各种瘦素在体内的功能意义， 受体池在血管疾病和了解肥胖对心血管并发症的影响有重要意义。

Obesity, is epidemic in the United States and is emerging as a strong independent risk factor for complications of atherosclerotic vascular disease such as myocardial infarction and stroke. Since thrombosis overlying an atherosclerotic plaque is the immediate cause of myocardial infarction and stroke, the obese state may promote the development of thrombosis at sites of vascular disease. Leptin, a hormone produced by the adipocyte, increases with obesity and may be one of the mediators responsible for the increased cardiovascular risk associated with obesity. We have recently demonstrated that leptin or leptin receptor deficiency is protective against thrombosis in a mouse model of arterial injury. Furthermore, this protective effect of leptin deficiency on thrombosis is reversed with leptin replacement. Consistent with a prothrombotic effect of leptin in humans, a recent clinical trial has demonstrated that elevated plasma leptin is an independent risk factor for cardiovascular events. The goals of this proposal are to characterize the impact of varying elevations of ieptin on thrombosis and atherosclerosis using established mouse models. In addition, mice with plateiet and endothelial leptin receptor deficiency will be generated using the Cre-loxP system to determine the relevant target tissues involved in mediating the adverse vascular effects of leptin. These studies will determine the functional in vivo significance of leptin and various leptin receptor pools in vascular disease and have important implications for understanding the effects of obesity on cardiovascular complications.