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 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 over-expression on vascular proteoglycan synthesis, lipoprotein retention and atherosclerosis development using in vivo methodology. 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. Program Director/Principal Investigator (Last, First, Middle): Tannock, Lisa R.
Obesity, metabolic syndrome, and diabetes are all associated with high rates of cardiovascular disease, and are characterized by modestly but chronically elevated levels of inflammatory markers including SAA. However, it is not currently known if high levels of SAA cause atherosclerosis, or merely indicate the amount of atherosclerosis already present. The goal of this proposal is to determine if elevated SAA has a role in causing atherosclerosis, which could lead to the identification of SAA as a new target for medical therapy to decrease atherosclerosis and cardiovascular disease
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| Tannock, Lisa R (2014) Vascular proteoglycans and atherosclerosis: not over yet. Atherosclerosis 237:435-6 |
| De Beer, Maria C; Wroblewski, Joanne M; Noffsinger, Victoria P et al. (2014) Deficiency of endogenous acute phase serum amyloid A does not affect atherosclerotic lesions in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 34:255-61 |
| Jahangiri, Anisa; Wilson, Patricia G; Hou, Tianfei et al. (2013) Serum amyloid A is found on ApoB-containing lipoproteins in obese humans with diabetes. Obesity (Silver Spring) 21:993-6 |
| King, Victoria L; Thompson, Joel; Tannock, Lisa R (2011) Serum amyloid A in atherosclerosis. Curr Opin Lipidol 22:302-7 |
