Collagen Gene Expression and Atherosclerosis

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Atherosclerotic lesions are characterized by infiltrating monocytes/macrophages, lymphocytes and smooth muscle cells (SMC). SMCs migrate from the medial layer to the vessel's intima, where they proliferate and deposit extracellular matrix components with collagen as the major component. Lipid infiltration at the site of lesion formation is prominent extracellularly and intracellularly. SMC and monocyte/macrophage lipid accumulation results in characteristic "foam cell" formation, which contributes to lesion formation. The collagen cap in a fibrous lesion is critical to stabilization of the plaque. Decreased collagen synthesis and/or increased collagen degradation by matrix metalloproteinases (MMPs) compromises the stable plaque, leading to rupture. This proposal will address factors that might influence SMC collagen gene expression in the lesion. Interferon-gamma (IFN-gamma), which is secreted by T lymphocytes, decreases collagen gene transcription and activates major histocompatibility class II (MHC II) gene transcription by inducing synthesis of the class II transcriptional activator, CIITA. The statins are a class of drugs used to decrease hypercholesterolemia via their ability to inhibit the enzyme, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies suggest that these agents have a greater beneficial effect in cardiovascular disease beyond their cholesterol lowering activity, in part, through their anti-inflammatory properties. Interestingly, they block IFN-gamma induced activation of MHC-II by inhibiting CIITA. We have recently demonstrated that CIITA interacts with an RFX5-complex at an RFX binding site located within the transcription start site of the collagen alpha2(I) gene leading to repression of collagen gene transcription by CIITA. Since statins also increase collagen gene expression, we hypothesize that the statins cause increased collagen synthesis in plaques by blocking IFN-gamma induction of CIITA. In addition, c-Abl interacts with RFX-1 and represses collagen synthesis when cells are not stimulated by IFN-gamma. RFX1 binds with high affinity to the collagen gene transcription start site when the DNA is methylated, and it can repress collagen gene transcription. The collagen gene is methylated at the RFX site in highly proliferating cancer cells that make low amounts of collagen. Therefore, we hypothesize that RFX1 interaction with c-Abl in the nucleus represses collagen gene transcription during SMC proliferation associated with plaque formation. In order to test our hypotheses, our specific aims are to 1. Investigate CIITA-mediated- regulation of collagen type I gene transcription by SMCs 2. Examine whether statins increase collagen type I gene expression by blocking IFN-gamma, induction of CIITA. 3. Determine if changes in proliferation by statins alter the interaction of c-Abl with RFX1 or collagen gene methylation status and expression and 4. Study collagen type I expression and accumulation in vascular lesions in vivo.