This proposal aims at evaluating the role of prenylcysteine lyase (PCL1), a new lipoproteinassociated protein, in atherosclerosis. Our finding that PCL1 carried by human atherogenic lipoproteins can itself generate an oxidant which in turn induces lipoprotein oxidation, and that its gene deletion reduces murine atherosclerotic lesion size, suggest a new role for PCL1 in the development of atherosclerosis. We will therefore study the properties of this protein, including the regulation of its gene expression and the chemical and functional changes induced on lipoproteins by PCL1 deletion, and we will explore what is the impact of PCL1 on
the development of atherosclerosis, its progression and/or the incidence of cariovascular events in human. Thus we will try to elucidate whether the new enzyme is a new risk factor for cardiovascular disease, hopefully paving the way to the development of new drugs that inhibit PCL1 activity and block the atherogenic modification of lipoproteins.