Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 8588252
• 负责人: Arturo J Cardounel
• 金额: $ 29.09万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588252
• 关键词: Affect; American; Amino Acids; Anabolism; Animal Model; Antiatherogenic; Arginine; Atherosclerosis; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cell physiology; Citrulline; Clinical Research; DNA; Development; Disease; Endothelium; Enzymes; Generations; Genetic Transcription; Goals; Grant; Homeostasis; Hydrolase; Impairment; In Vitro; Injury; Laboratories; Lead; Mediating; Metabolic; Metabolism; Methylation; Molecular; Morbidity - disease rate; N,N-dimethylarginine; Nitric Oxide; Nitric Oxide Synthase; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasma; Play; Post-Translational Protein Processing; Production; Protein-Arginine N-Methyltransferase; Proteins; Proteolysis; Public Health; Quality of life; Regulation; Research; Research Support; Role; Signal Transduction; Testing; Transferase; Vascular Diseases; Vasodilator Agents; dimethylarginine; endothelial dysfunction; enzyme activity; improved; in vivo Model; inhibitor/antagonist; insight; mortality; novel; novel strategies; protein function; therapeutic target

The long term objective of this proposal is to establish Protein Arginine Methyltransferases and Dimethyarginine Dimethylaminohydrolase (DDAH), the enzymes responsible for methylarginine synthesis and metabolism, as a key regulator of endothelial function. It is our hypothesis that the increased plasma ADMA observed in cardiovascular disease is a biomarker of DDAH activity and that many of the endothelial affects attributed to ADMA are directly manifested through altered DDAH-PRMT activity. We have shown that in addition to the direct effects of ADMA on eNOS activity, DDAH modulates endothelial NO production through ADMA independent mechanisms involving altered protein-methylation and amino acid metabolism. The goals of the current proposal are to: 1.) identify the pathways of ADMA metabolism in the endothelium; 2.) determine the mechanisms through which DDAH modulates endothelial protein-arginine methylation and define the effects of protein methylation on endothelial function; 3.) determine the mechanisms through which DDAH regulates endothelial L-arginine metabolism and the consequences on endothelial NO production; and 4.) identify the mechanisms through which the PRMT-DDAH-ADMA axis regulates endothelial function and atherosusceptibility. For each of these aims, a combination of cellular, molecular, biophysical and physiological approaches will be used to characterize the effects of DDAH on endothelial function using in vitro and in vivo models. Results from these studies will provide fundamental mechanistic information regarding the mechanisms through which the PRMT-DDAH-ADMA axis modulates cellular function and may lead to new approaches to treat vascular disease.

本提案的长期目标是建立蛋白质精氨酸甲基转移酶和