The proposal addresses the thesis that chronic inflammatory diseases - common in an ageing population - accelerates the development of atherosclerosis. During the acute phase response, serum amyloid A protein (A-SAA), an apolipoprotein, increases 1,000 fold and becomes a major component of high density lipoprotein (HDL). In spite of intense modern interest in the HDL particle, the teleological role of this alteration of HDL apolipoprotein composition during inflammation is unknown. We propose that A-SAA mediate the remodelling of HDL to accommodate a modified physiological requirement for this particle during inflammation namely phospholipid delivery to sites of inflammation. Chronic persistence of A-SAA render HDL less capable of mediating reverse cholesterol transport and to protect low density lipoprotein against oxidative modification providing an explanation for the increased mortality of patients with chronic inflammatory disease from cardiovascular disease. In addition to the acute phase A-SAA subfamily, we have identified new apolipoprotein molecules in man (C-SAA) and mouse (SAA5) as members of what now constitutes a SAA family. These form a distinct subfamily differing from A-SAA in structure and the fact that they are constitutive on normal HDL where they represent more than 95% of total SAA on this particle. We propose that these play a role in the function of this particle in the healthy state by promoting lipid exchange between lipoprotein particles. Given the centrality of HDL in lipoprotein metabolism and its dynamic interaction with other lipoproteins, experiments in the animal model is essential to complement more mechanistic studies. We propose to use transgenic mice that we have generated to study the interplay between the two sub families of the SAA superfamily and how they influence HDL impacting on other lipoproteins and whether there presence on HDL promotes atherosclerosis.
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