Aged vascular cells show greater reactivity to pro-atherogenic factors as compared to their young counterparts. Currently, the mechanism responsible for the age-related increase in the sensitivity of vascular cells to atherogenic stimuli has not been fully understood. There are indicators that reactive oxygen species (ROS), which increase with age, function as intracellular messengers of various stimuli to induce atherogenic responses in vascular cells. In this project, we will use transgenic mouse models that overexpress Cu/Zn-superoxide dismutase (SOD) or catalase alone or overexpress Cu/Zn-SOD and catalase in combination to test the following hypothesis: ROS contribute to the age-related increase in the sensitivity of endothelial cells (ECs) to oxidized lipids. We have chosen to test the sensitivity of ECs to oxidized lipids because oxidized lipids have been shown to have various atherogenic actions, e.g., inducing EC death, increasing leukocyte adhesion to ECs and reducing endothelial nitric oxide (NO). We have chosen to use mice overexpressing Cu/Zn-SOD and/or catalase because the atherogenic action of oxidized lipids is, at least in part, associated with its ability to induce ROS, e.g., superoxide and hydrogen peroxide, in ECs. Cu/Zn-SOD is a major enzyme to convert intracellular superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. This project contains three specific aims: 1) to study if overexpression of Cu/Zn-SOD and/or catalase attenuates age-related changes in endothelial NO metabolism; 2) to study if overexpression of Cu/Zn-SOD and/or catalase reduces age-related increase in oxidized lipid-induced adherence of leukocytes to ECs; 3) to study if overexpression of Cu/Zn-SOD and/or catalase reduces age-related increase in oxidized lipid-induced apoptosis in ECs. If the hypothesis described above is correct, reduction in intracellular superoxide and hydrogen peroxide by overexpression of Cu/Zn-SOD and/or catalase will attenuate the age-related increase in the sensitivity of ECs to oxidized lipids. Such information is important for understanding the role of ROS in the age-related development of atherosclerosis and could lead to potential strategies of therapy for atherosclerosis.

K01HL076623

2004-05-01

2009-03-31