The molecular and cellular mechanisms underlying hypertension as a risk factor for atherosclerosis are poorly understood. Several lines of clinical and experimental evidence suggest a potential role of the renin-angiotensin system in contributing to atherogenesis. Infiltration of monocytes into the vascular wall is a key initial step in the formation of the atherosclerotic lesion. Monocyte chemoattractant protein-1 (MCP-1), is a peptide chemokine that plays an important role in monocyte recruitment into the vessel wall. Angiotensin II (Ang II), a key component of the renin-angiotensin system, incudes vascular oxidative stress and second messenger signals that mediate vascular inflammatory events. The PI has demonstrated: 1) Rats infused with angiotensin II (Ang II) exhibit increased expression of vascular inflammatory genes such as MCP-1 in their aortas. 2) Ang II also induces MCP-1 gene expression in cultured rat aortic smooth muscle cells (VSMCs) through an oxidation-reduction sensitive mechanism. These data suggest that Ang II may contribute to atherogenesis by directly stimulating vascular inflammatory responses and promoting infiltration of inflammatory cells into the atherosclerotic lesion. The long- term goal of this project is to investigate the molecular mechanisms of regulation of chemokine gene expression in the vasculature, which may lead to the development of novel interventional methods for controlling the expression of these genes. This study is designed to investigate the molecular and signal transduction mechanisms that regulate Ang II-mediated MCP-1 gene expression using VSMCs as a model system. The PI will use molecular biology techniques to identify and characterize the cis-response element(s) and the trans-activating factor(s) involved in Ang II-induced MCP-1 gene expression in VSMCs. The PI will also use pharmacological intervention and genetic manipulation techniques to investigate the role of the transcription factors NK-kB and AP-1 in Ang II-induced MCP-1 gene expression in VSMCs. Furthermore, the PI will use similar approaches to characterize the specific oxidant signaling mechanisms involved in Ang II-induced MCP-1 gene expression in VSMCs. The information obtained would 1) help understand the molecular and cellular mechanisms in the regulation of MCP-1 gene expression in vascular smooth muscle cells, and 2) be useful in designing new interventional methods to prevent and control vascular inflammatory processes such as atherosclerosis.

R01HL060135

1998-08-14

2004-07-31