Abstract
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.
Highlights
Class A scavenger receptors (SR-A) have been implicated in the atherogenic process, there have been conflicting reports as to their specific effect on the development of lesions
There were no overt differences in the appearance or general health of non-transgenic or lyso bovine SR-A (bSR-A) repopulated LDLrϪ/Ϫ mice
Engraftment was verified by PCR detection of the LDL receptor (LDLr) gene in the bone marrow of all irradiated mice, as was the presence or absence of the bSR-A transgene (Fig. 1)
Summary
Class A scavenger receptors (SR-A) have been implicated in the atherogenic process, 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. A third strategy uses the chicken lysozyme promoter that has been shown to drive macrophage-specific gene expression in both transgenic mice [25] and rabbits [26, 27]
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