Regulation of mRNA Stability in Vascular smooth Muscle

University Of Rochester, Rochester NY

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Abstract

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