During the past few years, it has become apparent that reactive oxygen species (ROS) are involved in regulating specific cellular processes. An important finding from our own research program and other laboratories is that vascular cells produce superoxide anion (.02-) and that the major source of .02- in vascular tissues is a membrane-bound, NADH/NADPH- dependent oxidase. The importance of production of .02- and other oxygen radicals by vascular cells has been poorly defined. A major goal of this research program is to define these interactions. One of the project leaders in this PPG, Dr. Kathy Griendling, has cloned a component of the vascular smooth muscle oxidase, p22phox, and has shown that both over expression and inhibition of expression by antisense approaches respectively increases and decreases NADH oxidase activity. Activity of this oxidase is increased both in cell culture and in intact animals by angiotensin II (ang II). In project I, Dr. Griendling will determine the signaling mechanisms responsible for NADH/NADPH oxidase activation both in vitro and in vivo, and will establish the relationship of oxidase activation to vascular smooth muscle hypertrophy. She will also use the baculovirus-expressed p22phox to clone other components of this vascular oxidase system. In Project 2, Dr. Harrison will examine several aspects of the role of vascular .02- production and interactions of .02- with NO. in intact animals as these phenomena relate to blood pressure regulation, vascular reactivity, and activity and expression of matrix metalloproteinases. These experiments will involve use of transgenic mice in which p22phox expression is both increased and inhibited. In project 2, Drs. Alexander and Taylor will examine the effects of mechanical stretch on the production of ROS and modulation of vascular inflammation. Preliminary data indicate that expression of a critically important inflammatory molecule, monocyte chemoattractant protein-1 (MCP-1), is increased in a redox-sensitive fashion by stretch in cell culture and hypertension in vivo. The planned studies in project 3 will define the signaling pathways linking stretch, oxidative stress, and MCP-1 gene expression. Other studies, using mice lacking the MCP-1 receptor, will examine the functional significance of MCP-1 expression in hypertension. Overall, this research program will provide substantial new information defining the relationship between vascular oxidase activity and production of ROS and physiological and pathophysiological vascular events. Ultimately, this research may establish new concepts linking conditions which alter vascular oxidant stress and disease states such as hypertension and atherosclerosis.
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