ARRA: Role of Serum Amyloid A 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 atherosclerotic cardiovascular disease although the underlying mechanisms are not fully understood. The retention of atherogenic lipoproteins within the subendothelial space of the arterial wall by their interactions with vascular proteoglycans is thought to be a key step in the initiation of atherosclerosis, as outlined in the “Response to Retention Hypothesis”. Obesity, the metabolic syndrome and diabetes all are associated with increased levels of inflammatory markers including serum amyloid A (SAA), and SAA levels are predictive of cardiovascular disease in humans and in animal models. The central hypothesis of this grant is that SAA is pro-atherogenic. This hypothesis is based on several key observations: (a) SAA is present within atherosclerotic lesions in close association to apolipoproteins and proteoglycans. (b) We recently demonstrated that SAA alters vascular proteoglycan synthesis in a pro-atherogenic manner. (c) SAA is an apolipoprotein that is capable of binding to proteoglycans, and thus may facilitate the retention of lipoproteins on which it is carried. (d) In preliminary studies we demonstrate accelerated atherosclerosis in obese mice with elevated SAA, and in mice in which SAA is over-expressed. Thus, SAA may in fact be a mediator of atherosclerosis by leading to increased retention of atherogenic lipoproteins by vascular proteoglycans. We will test this hypothesis by evaluating the effect of SAA on lipoprotein retention and foam cell formation using in vitro and in vivo methodology. Furthermore, by using murine models of SAA over-expression and SAA deficiency, we will directly determine if SAA promotes atherosclerosis. Given the increased SAA levels observed in obesity, metabolic syndrome and diabetes, we propose that SAA may be a mechanism contributing to the increased cardiovascular disease in these conditions.