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Journal of Lipid Research, Vol. 43, 1201-1208, August 2002
Copyright © 2002 by Lipid Research, Inc.

Macrophage-specific expression of class A scavenger receptors in LDL receptor^-/- mice decreases atherosclerosis and changes spleen morphology

Stewart C. Whitman^1,*, Debra L. Rateri^*, Stephen J. Szilvassy, Joseph A. Cornicelli and Alan Daugherty^2,*

^* Gill Heart Institute, Division of Hematology/Oncology, University of Kentucky, Lexington, KY 40536
Division of Cardiovascular Medicine, and Blood and Marrow Transplant Program, Division of Hematology/Oncology, University of Kentucky, Lexington, KY 40536
Pfizer Global Research and Development, Ann Arbor Laboratories, Cardiovascular Therapeutics, 2800 Plymouth Road, Ann Arbor, MI 48105

² To whom correspondence should be addressed. e-mail: adaugh{at}uky.edu

Class A scavenger receptors (SR-A) have been implicated in the atherogenic process, although there have been conflicting reports as to their specific effect on the development of lesions. In part, this discord may arise because of the variable contribution of SR-A in the several cell types known to express this protein. To determine the effects of macrophage-specific SR-A expression in the atherogenic process, transgenic mice were created using the chicken lysozyme (lyso) promoter to drive expression of bovine SR-A (bSR-A). To express this gene in an atherosclerosis-susceptible strain, bone marrow cells from transgenic and non-transgenic littermates were used to repopulate lethally-irradiated female LDL receptor (LDLr)^-/- mice. Following hematopoietic engraftment, mice were placed on a diet enriched in saturated fat and cholesterol. After 8 weeks, there was a modest, but statistically significant reduction in serum total cholesterol in LDLr^-/- mice repopulated with lyso-bSR-A transgenic cells, due to decreased LDL-cholesterol. The extent of atherosclerosis was reduced in both cross-sectional analysis of the aortic root and en face analysis of the intimal surface of the aortic arch. In addition to changes in atherosclerosis, lyso-bSR-A repopulated LDLr^-/- mice had a marked increase (3.6x) in spleen weights and a disruption of spleen white pulp formation.

Therefore, macrophage-specific overexpression of SR-A resulted in reduced atherosclerosis in two vascular beds, reduced serum cholesterol concentrations, and changed the morphology of the spleen.

Abbreviations: BMT, bone marrow transplant; lyso, lysozyme; SR-A, class A scavenger receptors

Supplementary key words bone marrow transplantation • low density lipoprotein • immune function

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