Abstract
Although serum amyloid A (SAA) is an excellent marker for coronary artery disease, its direct effect on atherogenesis in vivo is obscure. In this study we investigated the direct effect of SAA on promoting the formation of atherosclerosis in apolipoprotein E-deficient (ApoE⁻/⁻) mice. Murine SAA lentivirus was constructed and injected into ApoE⁻/⁻ mice intravenously. Then, experimental mice were fed a chow diet (5% fat and no added cholesterol) for 14 wks. The aortic atherosclerotic lesion area was larger with than without SAA treatment. With increased SAA levels, the plasma levels of interleukin-6 and tumor necrosis factor-α were significantly increased. Macrophage infiltration in atherosclerotic regions was enhanced with SAA treatment. A migration assay revealed prominent dose-dependent chemotaxis of SAA to macrophages. Furthermore, the expression of monocyte chemotactic protein-1 and vascular cell adhesion molecule-1 (VCAM-1) was upregulated significantly with SAA treatment. SAA-induced VCAM-1 production was detected in human aortic endothelial cells in vitro. Thus, an increase in plasma SAA directly accelerates the progression of atherosclerosis in ApoE⁻/⁻ mice. SAA is not only a risk marker for atherosclerosis but also an active participant in atherogenesis.
Highlights
Atherosclerosis is an important underlying pathologic condition of cardiovascular disease (CVD), the leading cause of morbidity and mortality worldwide [1]
To investigate whether serum amyloid A (SAA) is purely a risk marker for atherosclerosis or is an active risk factor in vivo, we examined the effect of high-level expression of SAA on atherosclerosis development by using apolipoprotein E-deficient (ApoE–/–) mice transfected with lentivirus to induce SAA overexpression
The plasma levels of SAA were higher for the lenti-SAA group than the lenti-null and saline control groups, so the SAA1 lentivirus was efficiently transfected in vivo (Table 2)
Summary
Atherosclerosis is an important underlying pathologic condition of cardiovascular disease (CVD), the leading cause of morbidity and mortality worldwide [1]. One marker is serum amyloid A (SAA), an acute-phase protein that is an excellent marker of inflammation and positively and significantly associated with prevalent CVD [2,3,4]. SAA is one of the major acute-phase proteins in vertebrates [5]. It is produced principally by the liver in response to acute inflammatory stimuli and its plasma concentration can increase by up to 100- to 1000-fold over the basal level [6]. Increased SAA levels mediated by a high-fat diet and cholesterol were found to be associated with increased atherosclerosis in mice [14], which provides a link between diet and inflammation. Recent studies have demonstrated that SAA can stimulate proteoglycan synthesis and induce endothelial dysfunction, which suggests a crucial role of SAA in atherosclerosis development [15,16]
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