Metabolism of Endothelial Dysfunction in Renal Disease

描述（由申请人提供）：心血管疾病（CVD）是终末期肾病（ESRD）患者死亡的主要原因。心血管疾病部分是由内皮功能障碍引起的。三种代谢途径在内皮功能的调节中起主要作用：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。我们将对这些代谢途径的体内稳态及其对肾脏患者和健康对照者内皮功能障碍的影响进行一项随机、对照、机制研究。还将探讨膳食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。我们假设l -精氨酸- no通路、蛋氨酸-同型半胱氨酸循环和ADMA动力学的代谢失调会导致内皮功能障碍，而精氨酸和叶酸的补充将改善这些通路的稳态。目的是：(1)通过持续静脉滴注稳定同位素示踪剂L4guanidino 15N2]精氨酸、L- 2h3 -甲基]蛋氨酸和L- I) 3C]蛋氨酸，评估CRD和ESRD患者和健康对照者一氧化氮的生物利用度：（L .a）全身一氧化氮和精氨酸合成率、蛋氨酸转甲基化、同型半胱氨酸再甲基化和转硫化、半胱氨酸氧化和全血谷胱甘肽合成率；L-' 3C]瓜氨酸和L-' 3C]半胱氨酸。（l.b）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)探索4周膳食补充(a)精氨酸或(b)叶酸对这些途径内稳态的调节作用。主要终点为NO生物利用度，预测变量为动力学参数。将使用最先进的质谱技术和血管成像技术。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心血管疾病结局。

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.