Metabolism of Endothelial Dysfunction in Renal Disease

描述(申请人提供)：心血管疾病(CVD)是终末期肾病(ESRD)患者的主要死亡原因。心血管疾病的部分原因是血管内皮细胞功能障碍。在血管内皮细胞功能的调节中有三条代谢途径：L-精氨酸-一氧化氮途径、蛋氨酸-同型半胱氨酸循环和不对称二甲基精氨酸。这项应用是一项综合性研究，旨在整合肾脏患者内皮功能障碍的代谢、营养、生理和遗传方面。我们将进行一项随机、对照、机械性的研究，研究这些代谢途径在体内的动态平衡，以及它们对肾脏病患者和健康对照组内皮功能障碍的影响。补充精氨酸和叶酸对这些代谢途径的影响也将被探讨。相关的酶基因(MTHFR和DDAH)将与代谢表型相关。我们假设，L-精氨酸-NO途径、蛋氨酸-同型半胱氨酸循环和ADMA动力学的代谢失调导致内皮功能障碍，补充精氨酸和叶酸将改善这些途径的同源代谢。其目的是：(1)通过持续静脉滴注稳定的同位素示踪剂精氨酸、L-2H3-甲基蛋氨酸和L-I)，评估一氧化氮在慢性阻塞性肺疾病和终末期肾病患者和健康对照组中的生物利用度：(L.A)全身一氧化氮和精氨酸合成速率、蛋氨酸转甲基化、同型半胱氨酸再甲基化和硫化、半胱氨酸氧化和全血谷胱甘肽合成速率。(L.b)血浆不对称二甲基精氨酸(ADMA)浓度和DDAH活性。(L.C)这些代谢参数在三组间的差异。以及(2)探索为期4周的精氨酸或叶酸饮食补充对这些途径内稳态的调节作用。主要终点是无生物利用度，预测变量是动力学参数。将使用最先进的质谱学技术和血管成像。长期目标是获得关于这些过程的机制的新的和相关的知识，并最终改善这些患者的CVD结果。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death among End Stage Renal Disease (ESRD) patients. CVD is caused in part by endothelial dysfunction. Three metabolic pathways have a major role in the regulation of endothelial function: the L-arginine-Nitric Oxide (NO) pathway, the methionine-homocysteine cycle and the asymmetric dimethylarginine (ADMA). This application is a comprehensive study, aimed at integrating metabolic, nutritional, physiologic and genetic aspects of endothelial dysfunction in renal patients. We will conduct a randomized, controlled, mechanistic study on the in vivo homeostasis of these metabolic pathways, and their influence on endothelial dysfunction of renal patients, and in healthy controls. The influence of dietary supplementation with arginine and folic acid on these metabolic pathways will also be explored. Relevant enzymatic genotype (MTHFR and DDAH), will be correlated with the metabolic phenotype. We hypothesize that dysregulation of the metabolism of the L-arginine-NO pathway, the methionine-homocysteine cycle and ADMA kinetics contributes to endothelial dysfunction and that arginine and folic acid supplementation will improve homeostais of these pathways. The aims are: (1) to assess NO bioavailability in CRD and ESRD patients and in healthy controls in relation to: (l.a) whole body rates of NO and arginine synthesis, methionine transmethylation, homocysteine re-methylation and transulfuration, cysteine oxidation and the rates of synthesis of whole blood glutathione, by conducting primed, constant intravenous infusions of the stable isotope tracers L4guanidino 15N2] arginine, L-2H3-methyl]methionine and L- I) 3C]methionine;L-' 3Cureido]citrulline and L-' 3C]cysteine. (l.b) The plasma concentrations of the asymmetric dimethyl arginine (ADMA) and activity of DDAH. (l.c) The differences of these metabolic parameters across the three groups. And (2) To explore the regulatory effects of a 4-week dietary supplementation with (a) arginine or (b) folic acid on the homeostasis of these pathways. The primary endpoint is NO bioavailability and the predictor variables are the kinetic parameters. State-of-the-art mass spectrometric techniques and vascular imaging will be used. The long term objective is to gain new and relevant knowledge about the mechanisms of these processes and to eventually improve the outcome of CVD in these patients.