Metabolism of Endothelial Dysfunction in Renal Disease

描述（由申请方提供）：心血管疾病（CVD）是终末期肾病（ESRD）患者的主要死亡原因。CVD部分由内皮功能障碍引起。三种代谢途径在调节内皮功能中起主要作用：L-精氨酸-一氧化氮（NO）途径、蛋氨酸-同型半胱氨酸循环和不对称二甲基精氨酸（ADMA）。本申请是一项综合性研究，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。我们将对这些代谢途径的体内稳态及其对肾脏患者和健康对照内皮功能障碍的影响进行随机、对照、机制研究。还将探讨补充精氨酸和叶酸对这些代谢途径的影响。相关酶基因型（MTHFR和DDAH）将与代谢表型相关。我们推测，L-精氨酸-NO途径的代谢失调，蛋氨酸-同型半胱氨酸循环和ADMA动力学有助于内皮功能障碍，精氨酸和叶酸补充剂将改善这些途径的稳态。其目标是：（1）评估CRD和ESRD患者和健康对照中NO的生物利用度，涉及：（1.a）NO和精氨酸合成、甲硫氨酸转甲基化、高半胱氨酸再甲基化和转硫化、半胱氨酸氧化的全身速率和全血谷胱甘肽的合成速率，通过进行稳定同位素示踪剂[L4胍基15 N2]精氨酸的引发、恒定静脉内输注，L-[2 H3-甲基]甲硫氨酸和L-[3C]甲硫氨酸;L-[3Cureido]瓜氨酸和L-[3C]半胱氨酸。 (l.b)测定血浆不对称二甲基精氨酸（ADMA）浓度和DDAH活性。 (l.c)三组间这些代谢参数的差异。（2）探讨4周补充精氨酸（a）或叶酸（B）对这些途径稳态的调节作用。主要终点是NO生物利用度，预测变量是动力学参数。将使用最先进的质谱技术和血管成像。长期目标是获得有关这些过程机制的新的相关知识，并最终改善这些患者的CVD结局。

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.