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.
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