Serum Amyloid A Facilitates Early Lesion Development in \u3cem\u3eLdlr\u3csup\u3e-/-\u3c/sup\u3e\u3c/em\u3e Mice

BACKGROUND: Atherosclerosis is a chronic inflammatory disorder, and several studies have demonstrated a positive association between plasma serum amyloid A (SAA) levels and cardiovascular disease risk. The aim of the study was to examine whether SAA has a role in atherogenesis, the underlying basis of most cardiovascular disease. METHODS AND RESULTS: Mice globally deficient in acute-phase isoforms Saa1 and Saa2 (Saa-/-) were crossed to Ldlr-/- mice (Saa-/-Ldlr-/-). Saa-/-Ldlr-/- mice demonstrated a 31% reduction in lesional area in the ascending aorta but not in the aortic root or innominate artery after consuming a high-fat, high-cholesterol Western-type diet for 6 weeks. The lesions were predominantly macrophage foam cells. The phenotype was lost in more mature lesions in mice fed a Western-type diet for 12 weeks, suggesting that SAA is involved in early lesion development. The decreased atherosclerosis in the Saa-/-Ldlr-/- mice occurred despite increased levels of blood monocytes and was independent of plasma lipid levels. SAA is produced predominantly by hepatocytes and macrophages. To determine which source of SAA may have a dominant role in lesion development, bone marrow transplantation was performed. Ldlr-/- mice that received bone marrow from Saa-/-Ldlr-/- mice had slightly reduced ascending aorta atherosclerosis compared with Saa-/-Ldlr-/- mice receiving bone marrow from Ldlr-/- mice, indicating that the expression of SAA by macrophages may have an important influence on atherogenesis. CONCLUSIONS: The results indicate that SAA produced by macrophages promotes early lesion formation in the ascending aorta