PLATELET ACTIVATION WITH OBESITY PROMOTES ATHEROTHROMBOTIC VASCULAR EVENTS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖与心血管死亡风险增加相关，与其他公认的后果如高血压和高脂血症无关。导致心血管死亡的一个潜在因素可能与脂肪量增加诱导的促血栓形成和促炎症状态有关，这两者都是动脉粥样硬化临床表现发病机制的关键组成部分。血小板在动脉血栓形成中起核心作用，在炎症状态下被激活，并直接受到特定脂肪因子的影响，因此有可能作为肥胖心血管后果的重要介质。与此一致，肥胖与血小板聚集增加、血小板活化标志物如P-选择素的表面表达升高和血小板微粒形成增加有关。更重要的是，脂肪量的减少导致血小板活化增强标志物的正常化。然而，血小板过度活化在肥胖相关心血管疾病中的因果作用仍有待确定。血小板的几个特性和已证实的生物活性使其成为引发和维持肥胖炎症反应的有吸引力的候选者。活化而非静息血小板能够通过诱导单核细胞趋化蛋白（MCP-1）的分泌来改变内皮细胞的趋化特性。类似地，转化生长因子- B（TGF-B）从活化的血小板α-颗粒释放，并且已经显示增加1型纤溶酶原激活物抑制剂（派-1）从脂肪组织的释放。重要的是，最近的一份报告指出，脂肪组织中炎症细胞的募集是由血小板沿着沿着促进的。基于这些观察结果，我们提出了一个中心假设，即继发于肥胖的血小板活化在触发和维持肥胖的促炎和促血栓形成状态中起着因果作用，产生了一个涉及脂肪组织、活化血小板和血管内皮的反馈回路，最终在一个有利于动脉粥样硬化血栓形成血管事件的环境中达到高潮。 我们将检验我们的中心假设，并描述血小板活化导致肥胖症的炎症和血栓形成的机制，具体目标如下：（1）确定血小板在脂肪组织炎症反应中的作用;（2）确定血小板分泌在饮食诱导的肥胖症的促炎症和促血栓形成中的作用;（3）探讨血小板Toll样受体4信号通路在肥胖症炎症反应中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is associated with an increased risk of cardiovascular death independent of its other recognized consequences such as hypertension and hyperlipidemia. One potential contributing factor to this excess in cardiovascular deaths may be related to the pro-thrombotic and pro-inflammatory states induced by increases in adipose mass, both of which are critical components of the pathogenesis of the clinic manifestations of atherosclerosis. Platelets play a central role in arterial thrombosis, are activated in inflammatory states, and are directly influenced by specific adipokines, and therefore have the potential to serve as an essential mediator of the cardiovascular consequences of obesity. Consistent with this, obesity has been associated with increases in platelet aggregation, elevations in surface expression of markers of platelet activation such as P-selectin, and heightened platelet microparticle formation. More importantly, reduction in adipose mass leads to normalization of markers of enhanced platelet activation. However, a causal role for platelet hyperactivation in obesity-related cardiovascular disorders remains to be established. Several characteristics and proven biological activities of platelets make them an appealing candidate for triggering and maintaining the inflammatory response of obesity. Activated, but not resting platelets are able to alter the chemotactic properties of endothelial cells by inducing the secretion of monocyte chemoattractant protein (MCP-1). Similarly, transforming growth factor- b (TGF-b) is released from activated platelet a-granules and has been shown to augment the release of type-1 plasminogen activator inhibitor (PAI-1) from adipose tissue. Importantly, a recent report indicates that the recruitment of inflammatory cells in adipose tissue is facilitated by platelet adhesion along activated endothelium. Based on these observations, we propose the central hypothesis that platelet activation secondary to obesity plays a causal role in triggering and maintaining the pro-inflammatory and pro-thrombotic state of obesity, creating a feedback loop involving adipose tissue, activated platelets and vascular endothelium that culminates in an environment favorable for atherothrombotic vascular events. We will test our central hypothesis and delineate mechanism(s) by which platelet activation contributes to the inflammatory and thrombotic consequences of obesity in the following specific aims: (1) To identify the role for platelets in the inflammatory response of adipose tissue; (2) To establish a role for platelet secretion in the pro-inflammatory and pro-thrombotic consequences of diet-induced obesity; (3) To determine the role platelet toll-like receptor 4 signaling on the inflammatory response in obesity.