Manipulation of intracellular arginine content in endothelial cells

血管的内衬层（称为“内皮”）在控制血管功能方面起着至关重要的作用。最近有研究表明，心脏和血管疾病（吸烟、高血压、高胆固醇和糖尿病）、心脏病发作和心力衰竭的危险因素与内皮细胞功能异常有关。特别是，内皮维持血管处于松弛状态，防止血栓的形成（这可能导致心脏病发作和中风），防止血管增厚。内皮细胞的这些重要作用可以用一氧化氮（NO）的产生来解释，一氧化氮是一种小的化学信使，来源于一种在血液中循环的氨基酸——l -精氨酸。内皮细胞产生一氧化氮的数量很大程度上取决于可获得的精氨酸的数量，而这是由精氨酸进入细胞的数量和被精氨酸酶破坏（代谢）的数量之间的仔细平衡决定的。我们实验室开展的研究旨在了解精氨酸运输和精氨酸酶活性之间的重要平衡，作为确定预防和治疗心血管疾病新方法的基础。目前的提案描述了一系列研究，这些研究将使用这些系统的过度活性和不足活性的转基因模型，批判性地检查精氨酸运输和精氨酸酶活性的重要性。一旦确定，我们将测试操纵这些系统预防动脉粥样硬化的可能性。

The lining layer of blood vessels (termed the 'endothelium') plays a vital role in the control of blood vessel function. Recently it has been shown that risk factors for heart and vascular disease (smoking, high blood pressure, high cholesterol and diabetes), heart attack and heart failure are associated with an abnormally functioning endothelium. In particular, the endothelium maintains blood vessels in a relaxed state, prevents the formation of blood clots (which may cause heart attack and stroke) and prevents the thickening of blood vessels. These important actions of the endothelium are explained by the production of nitric oxide (NO) a small chemical messenger that is derived from an amino acid, L-arginine, which circulates in blood. The amount of NO produced by endothelial cells is very dependent on the amount of arginine available, and this is determined by a careful balance between the amount of arginine taken (transported) into cells and the amount that is destroyed (metabolized) by an enzyme called arginase. Research undertaken in our laboratory is directed at understanding the important balance between arginine transport and arginase activity, as a basis for identifying new ways to prevent and treat cardiovascular disease. The current proposal describes a series of studies which will critically examine the importance of arginine transport and arginase activity, using transgenic models of over-activity and under-activity of these systems. Once established we will test the possibility that manipulating these systems may prevent atherosclerosis.