Macrophage-specific expression of class A scavenger receptors in LDL receptor(-/-) mice decreases atherosclerosis and changes spleen morphology.
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.
Whitman
Stewart C
SC
Gill Heart Institute, Division of Hematology/Oncology, University of Kentucky, Lexington, KY 40536, USA.
Rateri
Debra L
DL
Szilvassy
Stephen J
SJ
Cornicelli
Joseph A
JA
Daugherty
Alan
A
D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D018955:CD36 Antigens / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A; D013154:Spleen / Q000473:pathology*
D018955:CD36 Antigens; D011973:Receptors, LDL; D051117:Scavenger Receptors, Class A