ROLE OF PROTEIN NITRATION AND NITRIC OXIDE

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DESCRIPTION (Adapted from Investigator's Abstract: Tyrosine nitration has been shown in various pathological conditions of the cardiovascular system including ischemia-reperfusion injury (Liu 1997, Wang 1996), atherosclerosis (Leeuwenburgh 1997), myocardial inflammation (Kooy 1997), and circulatory shock (Fukuyama 1997); however, the physiological relevance of tyrosine nitration remains unclear. Furthermore, very little is known about the formation and metabolism of nitrotyrosine in vivo, including the conditions that favor nitration, the specificity of nitration, the reversibility of nitration and the fate of nitrated proteins. They hypothesize that tyrosine nitration/denitration is a regulated process which participates in signal transduction. Thus, understanding the metabolism of nitrotyrosine is important. In this study, they propose to study the formation, degradation, and reversibility of nitrotyrosine. To study tyrosine nitration they will first examine the conditions which favor tyrosine nitration to determine which nitrating species are responsible for nitration in vivo. The contribution of peroxynitrite and the myeloperoxidase system from neutrophils and macrophages will be studied. They will then determine which proteins are nitrated in vivo. By purifying and characterizing proteins that are nitrated in vivo, they can determine which proteins are vulnerable to nitration. The specificity of tyrosine nitration may give them a clue as to the physiological relevance of nitration. The fate of nitrated proteins is also of interest. If tyrosine nitration contributes to inflammatory injuries, the degradation of nitrated proteins or the removal of the nitrate group may contribute to the reparation of these injuries. Therefore, in the third and fourth specific aims they have proposed to study the degradation of nitrated proteins and the reversibility of tyrosine nitration. These experiments are designed to examine the formation and metabolism of nitrotyrosine; thus, this project should contribute to our understanding of both the physiologic and the pathologic role of tyrosine nitration.