Abstract 480: Serum Amyloid A Acts Through TGF-ß to Increase Atherosclerosis in ApoE Deficient Mice

Abstract

Serum amyloid A (SAA), along with high sensitivity C- Reactive Protein, is a clinical marker of atherosclerosis, the leading cause of death in westernized countries. SAA is modestly but chronically elevated in several diseases such as diabetes and obesity that confer greater risk to developing atherosclerosis. It was recently reported that elevated SAA is pro-atherogenic in a murine model, although the mechanisms remain unclear. As outlined in the response to retention hypothesis, proteoglycan mediated lipoprotein retention is thought to be a key step in the initiation of atherosclerosis. We previously demonstrated in vitro that vascular smooth muscle cells treated with SAA had increased vascular biglycan synthesis with increased LDL binding affinity. We further demonstrated that SAA stimulation of biglycan was mediated via induction of TGF-β. To evaluate the pro-atherogenic effects of SAA in vivo, ApoE-/- male mice were injected with an adenovirus carrying the gene for human SAA1 (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. Although the SAA elevation was short, mice injected with adSAA had increased vascular biglycan content and significantly increased atherosclerosis at the aortic sinus (p<0.05) and en face aorta (P<0.001) compared to controls. SAA, apoB and biglycan co-localized within atherosclerotic lesions. To determine if TGF-β was required for the pro-atherogenic effects of SAA ApoE deficient mice received either a TGF-β neutralizing (1D11) or control antibody (13C4) simultaneously with injection of adSAA or adnull. The administration of TGF-β neutralizing antibody 1D11 prevented SAA-stimulated atherosclerosis but the irrelevant antibody 13C4 had no effect. Thus, in apoE-/- mice, SAA accelerates the development of atherosclerosis in a TGF-β[[Unable to Display Character: ]]dependent manner.