Role of the Inflammatory Cytokine Oncostatin-M in Promoting Atherosclerosis

Va Puget Sound Healthcare System, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Inflammation plays a major role in vascular diseases such as atherosclerosis, vein graft stenosis and proliferative restenosis following angioplasty and stent placement. A key step that facilitates many of the pathogenic roles of SMCs is phenotype modulation of vascular smooth muscle cells (SMC). Phenotype modulation of SMC involves down-regulation of SMC-specific genes, such as smooth muscle myosin heavy chain and calponin. The overall goal of this proposal is to define targetable mechanisms by which inflammatory mediators initiate SMC de-differentiation. The central hypothesis of this proposal is that activation of STAT-1 by inflammatory mediators is a necessary step for the development of advanced atherosclerotic lesions in vivo. To test these hypotheses, we propose two specific aims. Specific Aim 1: Test the hypothesis that the transcriptional factor STAT-1 promotes the development of atherosclerosis in ApoE-deficient mice. Specific Aim 2: Determine the role of OSM in the development of advanced atherosclerosis in ApoE- deficient mice. This proposed work will elucidate the role of an important biological factor, OSM, in the evolution of the atherosclerosis. It will also identify STAT-1 pathway as a therapeutic target for controlling pathological vascular remodeling.