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Genetic predisposition for atherosclerosis: nuclear receptors TR3, MINOR...

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Title Genetic predisposition for atherosclerosis: nuclear receptors TR3, MINOR and NOT as key regulators in protective mechanisms
Period 06 / 2005 - 11 / 2007
Status Completed
Research number OND1305615
Data Supplier Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)

Abstract

Background: Atherosclerosis, the underlying pathology of cardiovascular disease, is a progressive, chronic disorder being the major cause of morbidity and mortality in the elderly population. The initiation of atherosclerosis involves the invasion of monocytes into the activated vessel wall and the subsequent differentiation of these cells into macrophages. Macrophages, and more specifically the growth factors and cytokines released by these cells, are of crucial importance in the progression of atherosclerosis. The final conversion of macrophages into lipid-laden foam cells coincides with the retention of these cells as a structural component in atherosclerotic lesions. By genome-wide analysis we revealed that TR3 orphan receptor (TR3), Mitogen-induced nuclear orphan receptor (MINOR) and Nuclear orphan receptor of T-cells (NOT) are among the genes that are specifically induced in smooth muscle cells (SMCs) under atheroclerotic circumstances. These three genes form a separate subfamily of the nuclear receptor superfamily of transcription factors. We have shown that TR3, MINOR and NOT are expressed in human atherosclerotic lesions in smooth muscle cells (SMCs), endothelial cells and in macrophages. We have demonstrated that TR3 is a protective factor, which inhibits excessive SMC proliferation during vascular lesion formation in transgenic mice. Objectives: In the proposed research we will delineate the effect of TR3, MINOR and NOT on inflammatory signals of macrophages during atherogenesis both in vitro and in dedicated mouse models to further support the protective function of these key regulators in atherogensis. In addition, we will perform single nucleotide polymorphism (SNP) analyses for these genes in the Rotterdam Study population to demonstrate association with progression of atherosclerosis and risk of coronary heart disease. Approach: We will apply cultured primary human macrophages and THP-1 cells (human monocytic cell line) in which overexpression of TR3, MINOR, NOT and a dominant-negative variant of TR3, which inhibits all three transcription factors (TR3-dTA), will be mediated via lentiviral infection. To evaluate the macrophage characteristics that are relevant to atherosclerosis, in response to these transcription factors or their inhibitor, we will monitor macrophage differentiation, apoptosis, lipid uptake and expression of inflammatory mediators. Detailed gene expression profiling downstream of TR3-like factors will disclose unpredicted cell biological processes in which these nuclear receptors are involved. To study the function of TR3-like factors in lesion macrophages in vivo, we will overexpress TR3, MINOR, NOT or TR3dTA by means of lentiviral vehicles in bone marrow cells and perform bone marrow transplantations in mice with an atherosclerotic background (ApoE3Leiden). Subsequently, diet-induced vascular lesion formation will be monitored. We will evaluate the potential association of genetic polymorphisms in the genes encoding TR3, MINOR and NOT with the severity of atherosclerosis and risk of coronary heart disease. Several SNPs have been described in detail for NOT, of which some have been demonstrated to affect relative expression levels of this gene. SNPs described in the databases for TR3, MINOR and NOT will be selected based on functional relevance and novel polymorphisms will be revealed by sequence analyses. We will assess whether genetic variability in TR3, MINOR and NOT is involved in genetic predisposition for atherosclerosis and coronary heart disease in the Rotterdam Study. During the course of the project, also variation in selected genes downstream of the three transcription factors will be studied in the Rotterdam Study. Expected results: We anticipate that TR3, MINOR and NOT suppress the activation of macrophages, in analogy with the protective function of these transcription factors in endothelial cells and SMCs, and consequently inhibit progression of vascular lesion formation. We expect an association between severity of atherosclerosis and coronary heart disease with polymorphisms in the genes encoding these key regulatory proteins in endogenous feedback mechanisms against atherosclerosis.

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Project leader Prof.dr. H. Pannekoek

Classification

A70000 Public health and health care
D21400 Genetics
D21500 Histology, cell biology
D23220 Internal medicine
D24200 Health education, prevention

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