) Inflammation and thrombosis are two concurrent critical elements of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1), is a potent monocyte chemotactic factor and one of the most abundant proteins secreted by smooth muscle cells (SMC) and other cell types found in the atherosclerotic plaque. MCP-1 protein is induced in SMC in response to arterial injury and is also found in abundance in the plaque. Tissue factor, (TF), the initiator of the coagulation cascade, is also induced in vessel wall injury and found in the atherosclerotic plaque. TF is thought to be primarily responsible for the generation of thrombus in the injured vessel wall and on the ruptured plaque. The preliminary studies have demonstrated a novel function for MCP-1 as an inducer of TF in SMC and in THP-1 cells, a myelomonocytic cell line. They also have demonstrated specific and high affinity binding of MCP-1 on SMC. The only cell types that have been shown to have receptors for MCP-1 are monocytes, lymphocytes, basophils and eosinophils. Based on RT-PCR analyses, this SMC receptor appears to be distinct from the previously cloned monocytic receptor, CCR2A and B. The applicant hypothesizes that MCP-1 plays an important role in inducing TF in the vessel and therefore provides a link between the thrombotic and inflammatory components of atherosclerosis. This project will study the effects of MCP-1 on the induction of TF.
Aim 1 will determine the contribution of transcription and message stability to TF mRNA accumulation in response to MCP-1 and identify the cis-acting elements on the promotor that are responsive to MCP-1 and identify the protein kinase C isoforms involved.
Aim 2 will explore direct effects of MCP-1 on SMC migration, growth and activation of early response genes associated with coagulation.
Aim 3 will clone the SMC MCP-1 receptor using expression in Xenopus oocytes. Once this is accomplished, the cDNA will be used as a probe to examine the tissue distribution of the new MCP-1 receptor and study its regulation in SMC. The receptor will be expressed in COS cells to study the properties of the new receptor in mammalian cells and, in particular, to examine its coupling to TF induction.
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