Collagen Gene Expression and Atherosclerosis

Boston University Medical Campus, Boston MA

Investigators

Abstract

DESCRIPTION (provided by applicant): Atherosclerotic lesions begin as fatty streaks that can develop into mature lesions consisting of monocytes/macrophages, T lymphocytes and smooth muscle cells (SMCs), a necrotic core and a fibrous cap containing extracellular matrix components. Plaque rupture at the shoulder region and at sites of thinning in the fibrous cap overlying the lipid-rich core is a likely cause of myocardial infarction. This process is the result of chronic inflammation and is accompanied by cytokines, including interferon-gamma (IFN-y). IFN-y activates major histocompatibility class II (MHC II) gene transcription by inducing transcription of the class II transcriptional activator (CIITA). Recently, we have demonstrated that the collagen type I genes have an RFX binding site at the collagen type I transcription start sites and that RFX5 interacts with CIITA only after IFN-7 stimulation. Collagen synthesis is down regulated by CIITA and IFN-7 decreases collagen gene transcription through CIITA. Our hypotheses are that collagen repression occurs at the RFX site through cooperative interactions with CIITA and that INF-y stimulation of SMCs leads to lowered fibrous cap stability. An HMG-CoA reductase inhibitor, simvastatin, blocks IFNy-induced activation of MHC-II by inhibiting synthesis of CIITA. In addition to their well-known role in reducing lipid synthesis, statins increase collagen gene expression, reduce inflammation, inhibit cell proliferation, and decrease MMP accumulation in atheromas. We propose that these processes occur through the blocking of CIITA induction. We hypothesize that the statins lead to increased collagen synthesis by blocking IFN-gamma induction of CIITA through a lipid intermediate. RFX1 binds with high affinity to the methylated collagen gene transcription start site and can repress collagen gene transcription when over-expressed. The collagen gene is methylated at the RFX site in proliferating SMCs. Therefore, we hypothesize that, during SMC proliferation accompanying the development of aterhosclerotic lesions, the collagen gene is methylated, increasing binding of RFXI. 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-7 induction of CIITA and/or by blocking proliferation. 3. Study collagen type I expression and accumulation in vascular lesions in vivo using transgenic mice models.