Serum Amyloid A and Vascular Proteoglycans in Atherosclerosis

Cardiovascular disease is the leading cause of death in developed countries. Individuals with obesity, metabolic syndrome, and/or diabetes are at markedly increased risk of cardiovascular disease although the underlying mechanisms are not fully understood. Inflammation is a hallmark of atherosclerosis. Obesity, the metabolic syndrome and diabetes all are associated with increased levels of inflammatory markers including serum amyloid A (8M). 8M levels are predictive of cardiovascular disease in humans and in animal models. 8M is expressed within atherosclerotic lesions and accumulates in close association to apolipoproteins and proteoglycans. Vascular proteoglycans playa critical role in the initiation of atherosclerosis due to their ability to bind and retain atherogenic lipoproteins, as described in the response to retention hypothesis. 8M is an apolipoprotein that is capable of binding to proteoglycans, and thus may playa role in proteoglycan-lipoprotein interactions. Furthermore, we have preliminary data suggesting that 8M can alter proteoglycan synthesis in a manner that may affect their lipoprotein binding affinity. 8M has a number of properties that may playa direct role in atherogenesis, and thus 8M may in fact be a mediator of atherosclerosis rather than a marker of cardiovascular risk. The central hypothesis of this grant is that 8M is pro-atherogenic. We will investigate this hypothesis by evaluating atherosclerosis development in murine models of 8M overexpression, and 8M deficiency. We will also determine if 8M modulates lipoprotein-proteoglycan interactions. Given the increased 8M levels observed in obesity, metabolic syndrome and diabetes, we propose that 8M may be one mechanism linking these conditions with cardiovascular disease.