Regulation of mRNA Stability in Vascular smooth Muscle

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Monocyte chemoattractant protein-1 (MCP-1) is a chemokine secreted by endothelial cells, smooth muscle cells (SMC), and macrophages that plays a key role in recruiting macrophages to the arterial wall during the development of atherosclerosis. Platelet-derived growth factor (PDGF) is an activator of SMC and a potent inducer of MCP-1. The effect of PDGF on MCP-1 mRNA levels in SMC is due largely to a marked increase in mRNA half-life (t1/2). In contrast, the glucocorticoid dexamethasone (Dex) inhibits the accumulation of MCP-1 mRNA in a variety of cell types; in SMC this is due to a marked decrease in mRNA t1/2. The Dex effect appears to be dependent upon the glucocorticoid receptor (GR), but not on new transcription, suggesting a novel role for the GR. Although there is considerable information concerning the mechanisms by which PDGF and Dex regulate gene transcription, far less is known about their effects on mRNA stability. This proposal will examine the mechanisms by which PDGF and Dex regulate MCP-1 mRNA stability in cell culture and in vivo. Aim 1 will characterize the Dex-sensitive region of the MCP-1 mRNA, elucidate the mechanisms by which Dex destabilizes MCP-1 mRNA, and identify the proteins involved. Emphasis will also be placed on establishing the role of the GR in regulating MCP-1 mRNA stability. Similarly, aim 2 will characterize the mechanism by which PDGF enhances MCP-1 mRNA stability and identify the protein(s) involved. Aim 3 will examine the regulation of MCP-1 mRNA stability in animal models and will establish the effect of Dex on MCP-1-mediated events in vivo. It will also develop animal models for examining mediators of MCP-1 mRNA stability identified in aims 1 and 2. These studies will provide new insights into the regulation of MCP-1, the biology of PDGF and glucocorticoids, and the control of the inflammatory response in the arterial wall. It may also provide novel approaches to inhibiting MCP-1 expression and macrophage accumlation by mimicking the effect of Dex or by blocking the effect of PDGF on MCP-1 mRNA.