Recent insights into the cellular biology of atherosclerosis

Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy.

Abstract 446: Serum Amyloid A Is Proatherogenic

Serum amyloid A (SAA), along with high sensitivity C- Reactive Protein, is a clinical marker of atherosclerosis, a vascular inflammatory disease responsible for half a million deaths per year in the US. Interestingly, SAA is modestly but chronically elevated in several diseases such as diabetes and obesity that confer greater risk to developing atherosclerosis. Recently SAA has been shown to contribute to the progression of atherosclerosis but its role in initiation of atherosclerosis has yet to be determined. As outlined in the response to retention hypothesis of atherosclerosis, proteoglycan mediated lipoprotein retention is thought to be a key initiating step. We previously demonstrated that mice overexpressing SAA had increased vascular biglycan, a small matrix proteoglycan, which was larger and had greater LDL binding affinity than native biglycan. Here we tested the hypothesis that overexpression of SAA would lead to increased atherosclerosis. ApoE -/- male mice were injected with an adenovirus carrying the gene for SAA (adSAA), a null control (adnull) or saline and maintained on chow for 16 weeks. SAA was elevated immediately after injection of adSAA but returned to baseline by 10 days; there was no elevation of SAA in adnull or saline injected mice. Although the duration of elevation of SAA was short, mice injected with adSAA had significantly increased atherosclerosis at the aortic sinus (p<0.05) and en face aorta (P<0.0009) compared to controls. SAA, apoB and biglycan co-localized within atherosclerotic lesions. There was no difference in lipid levels, lipoprotein distribution, body weight or glycemic indices between groups. Thus, we now demonstrate that SAA accelerates atherosclerosis initiation, and we propose that SAA’s induction of vascular biglycan leading to increased lipoprotein retention is the mechanism.