Murphy, Nuala; (2002) Serum markers of atherogenesis in apoE*3 Leiden mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Atherosclerosis is a major cause of morbidity and mortality in Westernised societies. Unfortunately, the disease remains largely silent until clinical symptoms ensue. Secreted chemokines and shed forms of adhesion molecules are found in the circulation, and it was hypothesized that systemic levels of these molecules could prove useful 'markers' of the monocyte recruitment that characterises atheroma development. Serum concentrations of CC (JE/Monocyte Chemotactic Protein-1 [MCP-1]) and CXC (KC, Macrophage Inflammatory Protein-2 [MIP-2]) chemokines, and/or soluble adhesion molecules. Vascular Cell Adhesion Molecule-1 [VCAM-1] and Intercellular Adhesion Molecule-1 [ICAM-1], were measured during development of atherosclerosis in apoE*3 Leiden mice and their non-transgenic littermates, fed diets high in fat and cholesterol containing sodium cholate (HFC/C), deficient (HFC/LAO) or supplemented with (HFC/HAO) antioxidant vitamins. ApoE*3 Leiden mice developed marked hypercholesterolaemia and lesions that progressed from early Type I 'fatty streaks' to more complex fibrous plaques; by contrast, their non-transgenic littermates (C57BL/6J) exhibited a much less pronounced hypercholesterolaemia, and developed small fatty streak lesions, after consuming the same HFC/C diet. Interestingly, antioxidant vitamins signally failed to reduce atheroma development in either apoE*3 Leiden or non-transgenic mice fed HFC/HAO compared with HFC/LAO. Rapid increases in serum concentrations of KC appeared to be associated with early development of atheroma in apoE*3 Leiden mice fed diet HFC/C, compared with their non- transgenic littermates. By contrast, circulating levels of JE/MCP-1 were elevated to a similar degree in both groups of mice consuming the HFC/C diet, and coincided with development of hypercholesterolaemia. However, systemic JE and KC levels were unaffected by consumption of either HFC/HAO or HFC/LAO forms of this diet. Circulating levels of slCAM-1 were elevated in both apoE*3 Leiden mice, and the non- transgenic controls consuming HFC/C diet. Systemic levels of these molecules were sensitive to the presence of dietary antioxidants, with high levels of sVCAM-1 and slCAM-1 noted in non-transgenic mice consuming the HFC/LAO diet. Hepatic expression of JE and KC mRNA were detected by in-situ hybridisation in both groups of animals fed HFC/C diet. Aortic expression of JE mRNA, but not KC, mRNA was seen within macrophage-rich atherosclerotic lesions in apoE*3 Leiden mice. However, RT-PCR detected the presence of both JE and KC mRNA in aortic and hepatic tissues. In summary, it is clear that the systemic markers investigated in this thesis were not specific to atheroma and did not provide greater predictive value, in terms of lesion progression, than measurement of more established 'risk factors' such as serum cholesterol. The results suggest that multiple inflammatory sites may be involved in their production, consequent to the atherogenic diet and the development of gross hyperlipidaemia. Indeed, the atherogenic diet used may have masked any subtle differences in systemic chemokine and adhesion molecule concentrations that were caused directly by the atherosclerotic lesions.

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