MECHANISMS OF ENDOTHELIAL DYSFUNCTION IN OBESITY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肥胖是心血管疾病发展的独立危险因素，我国肥胖患病率呈上升趋势。肥胖如何导致心血管疾病尚不清楚。肥胖与内皮功能受损有关，这可能在心血管疾病的发病机制中起关键作用。本研究的长远目标是研究肥胖/胰岛素抵抗与内皮依赖性血管舒张之间的关系。我们建议的具体目的是研究内皮功能的变化，以应对1)提高游离脂肪酸水平，2)抑制交感神经系统活动，3)改善胰岛素抵抗。内皮功能将通过评估在股动脉内输注内皮依赖性血管扩张剂甲基胆碱氯、内皮非依赖性血管扩张剂硝普钠和内皮源性一氧化氮抑制剂ng -单甲基- l-精氨酸（L-NMMA）后的腿部血流量增量来确定。全身输注肝素可提高游离脂肪酸水平。交感神经系统的活动将被股动脉输注酚妥拉明（一种α肾上腺受体阻滞剂）所抑制。胰岛素抵抗可以通过减肥或使用胰岛素增敏剂曲格列酮来改善。这些研究将有助于更好地了解肥胖/胰岛素抵抗对内皮功能的影响，并可能有助于设计治疗策略，以降低这一人群患心血管疾病的风险。

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 an independent risk factor for the development of cardiovascular disease, and the prevalence of obesity is increasing in this country. How obesity causes cardiovascular disease is not understood. Obesity is associated with impaired endothelial function which may play a crucial role in the pathogenesis of cardiovascular disease. The broad, long term objective of this proposal is to investigate the relationship between obesity/insulin resistance and endothelium dependent vasodilation. The specific aims of our proposal are to study changes in endothelial function in response to 1) raising free fatty acid levels, 2) inhibition of sympathetic nervous system activity, and 3) amelioration of insulin resistance. Endothelial function will be determined by assessing the leg blood flow increments in response to intrafemoral artery infusion of the endothelium dependent vasodilator methacholine chloride, the endothelium independent vasodilator sodium nitroprusside, and the inhibitor of endothelium derived nitric oxide NG-monomethyl-L-arginine (L-NMMA). Free fatty acid levels will be raised by systemic infusion of intralipids with heparin. The sympathetic nervous system activity will be inhibited by a femoral artery infusion of phentolamine, an alpha adrenoreceptor blocker. Insulin resistance will be ameliorated by weight loss or by administration of the insulin sensitizer troglitazone. These studies will help to better understand the effect of obesity/insulin resistance on endothelial function and may help to design treatment strategies to decrease the risk for cardiovascular diseases in this population.