Manipulation of intracellular arginine content in endothelial cells

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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.