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. Endothelial dysfunction is a feature of the insulin resistant states of obesity and type 2 diabetes mellitus. The long-term goal of our laboratory is to better understand the interactions between metabolism and vascular function in order to improve therapy of metabolic diseases and their vascular complications. We have recently demonstrated that increased endothelin-1 (ET-1) action contributes to endothelial dysfunction in obesity and type 2 diabetes. It may therefore be desirable to reduce ET-1 action in order to improve endothelial function. However, the factors which cause this increased ET-1 action are unknown. In vitro and in vivo findings suggest that insulin and free fatty acids directly regulate endothelin, and our preliminary data suggests these metabolites may in fact contribute to increased ET-1 action in human obesity. Nitric oxide (NO) also exerts important inhibitory control over ET-1 in vitro, and therefore impaired NO bioactivity in vivo may also be an important contributor to increased ET-1 action. The effect of insulin to stimulate NO is reduced in obesity, and free fatty acids can directly impair NO production. It is therefore possible that insulin and free fatty acids influence endothelin activity directly, and/or indirectly via effects on NO. This distinction is important in that therapeutic approaches to reduce ET-1 action in obesity may or may not require specifically improving the metabolic state. The objective of this application is to define the roles of free fatty acids, insulin and nitric oxide in the regulation of ET-1 in obese and lean humans. The main hypothesis of this proposal is that the increases in circulating free fatty acids and insulin seen in obesity contribute directly to increased ET-1 action in human obesity. A second hypothesis is that impaired NO bioactivity is sufficient to explain increases in ET-1 action. A comparison of in vivo leg vascular response to endothelin antagonism alone and with concurrent increases or reductions in insulin, FFA, and/or NO will be used to assess the effect of these factors on ET-1 action in lean and obese humans. These studies use innovative approaches to study design in order to distinguish contributions of metabolites themselves from their effects on NO bioactivity, and the approach taken in order to achieve NO replacement.
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