Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 8245442
• 负责人: Arturo J Cardounel
• 金额: $ 32.38万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245442
• 关键词: Methylarginines; Vascular; Injury

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This research is relevant to public health since atherosclerosis is among the leading cause morbidity and mortality in Americans. Our research has discovered new cellular pathways that are involved in the development of vascular diseases. Research supported by this grant may help identify new drugs to treat arterial pathology and could improve the quality of life of people suffering from cardiovascular disease.

描述（由申请人提供）：本提案的长期目标是建立蛋白质精氨酸甲基转移酶和二甲基精氨酸二甲氨基水解酶（DDAH）（负责甲基精氨酸合成和代谢的酶）作为内皮功能的关键调节剂。我们的假设是，在心血管疾病中观察到的血浆 ADMA 增加是 DDAH 活性的生物标志物，并且 ADMA 引起的许多内皮细胞影响是通过 DDAH-PRMT 活性的改变直接表现出来的。我们已经证明，除了 ADMA 对 eNOS 活性的直接影响外，DDAH 还通过 ADMA 独立机制（涉及改变蛋白质甲基化和氨基酸代谢）调节内皮 NO 产生。当前提案的目标是：1）确定内皮细胞中 ADMA 代谢的途径； 2.) 确定 DDAH 调节内皮蛋白精氨酸甲基化的机制，并确定蛋白甲基化对内皮功能的影响； 3.) 确定DDAH调节内皮L-精氨酸代谢的机制以及对内皮NO产生的影响； 4.) 确定 PRMT-DDAH-ADMA 轴调节内皮功能和动脉粥样硬化易感性的机制。对于每个目标，将结合细胞、分子、生物物理和生理学方法，利用体外和体内模型来表征 DDAH 对内皮功能的影响。这些研究的结果将提供有关 PRMT-DDAH-ADMA 轴调节细胞功能的机制的基本机制信息，并可能导致治疗血管疾病的新方法。 公共健康相关性：这项研究与公共健康相关，因为动脉粥样硬化是美国人发病和死亡的主要原因之一。我们的研究发现了参与血管疾病发展的新细胞途径。这笔赠款支持的研究可能有助于确定治疗动脉病理学的新药，并可以改善心血管疾病患者的生活质量。