Activation of cell death pathways leading to endothelial cell apoptosis and neointimal vascular smooth muscle cell hyperplasia is an initial trigger of the progression of atherosclerotic lesions. Because apoptosis is a highly regulated cellular process and mediates the development of atherosclerotic plaques, targeted inhibition of endothelial cell apoptosis is an effective approach to the treatment of atherosclerosis. Scatter factor (SF) also known as hepatocyte growth factor (HGF) has been identified as a powerful endothelial specific anti apoptotic and mitogenic factors. These findings have important implications in the field of cardiovascular disease since SF/HGF stimulates growth of endothelial cells exclusively without replication of vascular smooth muscle cells and SF/HGF based therapies could be effective in the treatment of atherosclerosis. We have developed a small molecule mimetic of SF/HGF activity (c-met agonist) that was rationally designed through a novel combination of phage display and molecular modeling technology. Preliminary studies have revealed that this small molecule compound, designated as C6 has potent SF/HGF like activity. In vitro, C6 activates SF/HGF receptor, c-met to mediate biological functions of SF/HGF, such as renal cell scatter, endothelial cell proliferation, and cellular protection against apoptosis. In the proposed studies, we will evaluate the protective effects of our c-met agonist, C6 in atherosclerotic mouse models. We will further evaluate the biochemical and signal transduction pathways involved in inducing endothelial proliferation and the anti apoptotic effects of C6. The goal of our research is to develop a novel therapeutic strategy to modify endothelial cell survival and to reverse the progression of atherosclerotic plaque, which is characterized, by a progressive endothelial cell apoptosis and tissue fibrosis. These studies promise to provide fundamental, preclinical information about the feasibility and efficacy of C6 as a new therapeutic approach for atherosclerotic vascular disease. If successful, the data generated will be critical for future clinical development and optimization of C6 or other structurally related compounds that target endothelial apoptosis and regeneration.
