Influence of serum amyloid a on the development of atherosclerosis and monopoiesis.

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Bibliographic Details
Author / Creator:Krishack, Paulette A.
Description:182 p.
Format: E-Resource Dissertations
Local Note:School code: 0330.
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Other authors / contributors:University of Chicago.
Notes:Advisors: Catherine Reardon; Godfrey Getz.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Department of Pathology, 2015.
Dissertation Abstracts International, Volume: 76-08(E), Section: B.
Summary:Cardiovascular disease is one of the leading causes of death nationwide, with atherosclerosis being one the top contributing cause. It is currently recognized that atherosclerosis is a chronic inflammatory disorder initiated in response to hyperlipidemia. Studies have shown a positive association between the development of atherosclerosis and acute phase proteins, particularly serum amyloid A (SAA). However, it is unknown if SAA is involved in lesion development. To study the role of SAA in atherogenesis, Ldlr -/- mice globally deficient in acute phase isoforms SAA 1 and 2 (Saa-/-Ldlr-/-) and Ldlr-/- controls were fed a high-fat/high-cholesterol Western-type diet (WTD) for 6 and 12 weeks. A site-specific phenotype was found, with less atherosclerosis and lesional macrophages in the ascending aorta, but not in the innominate artery or aortic root after 6 weeks WTD. No differences were found in lesional area in more mature lesions after 12 weeks of WTD, indicating that SAA promotes early lesion development. Lesion development was independent of plasma lipid metabolism. Histological staining indicated that the 6 week lesions primarily consisted of macrophage foam cells. SAA is a secreted HDL-associated apolipoprotein produced by hepatocytes and macrophages. A 4 x 4 crossover design bone marrow transplantation was performed using Saa-/-Ldlr-/-and Ldlr-/- mice, which indicated that SAA produced by macrophages is more influential for lesional development. Interestingly, Saa-/-Ldlr-/- mice had higher levels of blood monocytes after 6 weeks WTD, the majority of which were Ly6clo monocytes, despite having reduced atherosclerosis. Thus, monocytosis did not contribute to the atherogenic phenotype. Both the presence and absence of SAA differentially regulate monopoiesis. The presence of SAA lowered CMP and GMP levels, while in the absence of SAA supported expansion of MDP levels after WTD feeding. Together, this resulted in a higher level of Ly6clo blood monocytes in Saa-/- Ldlr-/- mice fed WTD. Further studies are needed to determine how the presence and absence of SAA regulate monopoiesis.