Angiotensin II (Ang II) is a critical mediator of vascular inflammation and remodeling in a number of diseases including hypertension, atherosclerosis and diabetes. AngII effects on vascular wall function and morphology occur as a result of distinct changes in gene expression, that are at least in part dependent on the activation of the transcription factors NF-kB, and AP-1. Ets-1 is the prototypic member of the ETS family. Our results suggest that Ets-1 is a critical modulator of inflammatory responses in the vascular smooth muscle cells, endothelial cells and T cells, in response to inflammatory stimuli. Ets-1 is upregulated in response to PDGF-BB, Angiotensin II, and thrombin. Chronic infusion of AngII in mice promotes vascular remodeling that begins with the recruitment of inflammatory cells, followed by medial hypertrophy and perivascular fibrosis. Ets-1 deficient mice exhibit marked reductions in vascular remodeling compared to control mice in response to AngII. We have identified the chemokine MCP-1 as a major downstream target for Ets-1. Ets-1 deficient mice exhibit marked reduction in the expression of MCP-1 at sites of vascular inflammation. We have also identified the NAD(P)H isoenzyme phox47 as a downstream target of Ets-1. The overall hypothesis for this proposal is that the ETS transcription factor Ets-1 is a critical mediator of vascular inflammation and is therefore required for mediating inflammatory responses in a number of vascular diseases. The goals of these studies are to: 1) Characterize how Ets-1 is regulated by Ang II at the transcriptional, post-transcriptional, and post-translational levels. 2) Characterize the role of Ets-1 in the regulation of reactive oxygen species (ROS) and in particular the NAD(P)H oxidase isoenzyme phox47 in response to AngII and other inflammatory stimuli. 3) Test the therapeutic effect of systemic administration of dominant-negative forms of Ets-1 to block vascular inflammation 3) Determine the role of Ets-1 as a mediator of vascular inflammation and remodeling in specific cell types by generating conditional knockouts in vascular smooth muscle cells. The long-term goals of this proposal are not only to understand the molecular mechanisms of vascular inflammation but to thereby identify potential novel therapeutic approaches toward inhibiting this process.
Vascular inflammation is a critical component of several vascular diseases including hypertension, coronary heart disease, and diabetes mellitus. The goals of this project are to further define the role of the Ets-1 transcription factor in regulating vascular inflammation, and evaluate the therapeutic potential of dominant negative forms of this transcription factor to block several stages of vascular inflammation in mouse models of human disease.
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