application) The superoxide dismutases are a family of enzymes responsible for catalyzing the conversion of the superoxide anion (O2) to hydrogen peroxide. Of particular interest is an extracellular form of SOD (ecSOD), which is a copper/zinc tetramer produced by many cells, including smooth muscle cells. The biological importance of this enzyme has only recently become apparent. The studies that form the background of this grant indicate that in the setting of both atherosclerosis and hypertension, there is a substantial increase in expression of lipid-laden macrophages, which accumulate in atherosclerotic vessels. Interestingly, the increase in ecSOD protein is disproportionately large compared to a modest increase in ecSOD protein expression.
In Aim 1, studies will examine the effect of either unmodified or modified lipoproteins, lysophosphatidylcholine or linoleic hydroperoxide on expression of ecSOD in macrophages or vascular smooth muscle cells.
In Aim 2, the PI will examine the role of reactive oxygen species, including O2, hydrogen peroxide, and peroxynitrite in modulating vascular and macrophage ecSOD expression.
In Aim 3, the PI will examine the stability of the ecSOD protein in lipid-laden macrophages, control macrophages, and vascular smooth muscle cells and to determine how reactive oxygen species and either LDL influence this.
This aim i s based on their observation that the increase in ecSOD protein expression may occur via post-translational mechanisms.
In Aim 4, the effect of reactive oxygen species on the structure and activity of the ecSOD will be examined. These studies will involve examination of recombinant ecSOD, which the PI has expressed in a baculovirus/Sf9 system.
In Aim 5, the PI will examine mechanisms whereby hypertension increases expression of the ecSOD. These studies will be performed in normal and Apo(e)-deficient mice, and will utilize our ability to examine mRNA and protein expression in small amounts of protein expression in small amounts of tissues from these animals and should begin to provide new information regarding a potentially important modulator of oxidative phenomena in the arterial wall.
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