Oxidized lipids and/or oxidized lipoproteins accumulated in the arterial wall have been proposed to play a critical role in atherogenesis. Data from recent studies suggest that the atherogenic action of oxidized lipids is, at least in part, associated with its ability to induce reactive oxygen species (ROS) in vascular cells. Increased ROS in vascular cells are believed to induce expression of a variety of proteins that are thought to be involved in adherence of inflammatory cells to the endothelium, proliferation and death of vascular cells. The theory that ROS play a role in atherogenesis is attractive, but is still unproven. The goal of the research described in this project is to use transgenic animal models to test directly the following hypothesis: ROS play a role in atherogenesis by increasing lipid peroxidation and/or increasing the sensitivity of vascular cells to oxidized lipids. In this project, we will use transgenic mouse models that overexpress human Cu/Zn superoxide dismutase (Cu/Zn-SOD), human catalase or both Cu/Zn-SOD and catalase transgenes. We have chosen to use these mice because superoxide and hydrogen peroxide are proposed to be factors that play a role in both vascular cell-mediated lipid oxidation and oxidized lipid-induced atherogenic activities. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase will be crossbred into the apolipoprotein E (ApoE) knockout mice. The homozygous ApoE knockout mice accumulate oxidized lipids in the arterial wall and spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. This project consists of three specific aims: 1) to determine if overexpression of antioxidant enzymes reduces the development of atherosclerosis; 2) to determine if overexpression of antioxidant enzymes affects the response of vascular cells to oxidized lipids; and 3) to determine if overexpression of antioxidant enzymes reduces lipid peroxidation. If the hypothesis described above is correct, mice overexpressinq Cu/Zn-SOD and/or catalase will show reduced atherosclerotic lesions, which will correlate to a decreased accumulation of oxidized lipids in the arterial wall and/or a reduced response of vascular cells to oxidized lipids.

R15HL071525

2003-09-01

2005-12-31