The current study shows clear associations of serum lipid levels and ethnicity with macrophage SR gene expression. Thus, CD36 and MSR1 expression were both positively associated with serum LDL levels, and MSR1 was also negatively associated with HDL. Gene expression of CD68 was positively associated with serum triglyceride levels. In terms of the association of ethnicity with SR expression, CD68 was expressed at higher levels in subjects with European ancestry, whilst MSR1 was expressed at lower levels in African subjects.
When comparing data between the 3 ethnic groups, the African participants had significantly higher levels of both BMI and hip circumference compared to the other groups. It is known that obesity is more prevalent in African than other ethnic groups in South Africa, particularly in females (20). In addition, LDL and total cholesterol, although not statistically significantly so, were lower in the African compared to the other groups. Similar ethnic differences in lipid profiles have been reported in other South African studies (21, 22).
Scavenger receptors MSR1and CD36 have been shown to be the primary receptors responsible for the uptake of modified LDL into macrophages leading to foam cell formation (23) (2). The interaction of CD68 with modified lipoproteins is still controversial and their relevance is still unclear (2). However, a study by Tsukamoto and colleagues (2002) reported that CD68 may play a crucial role in foam cell formation through uptake of oxLDL by macrophages (24). In our study CD36 expression was lower in African and Indian compared to European participants, whereas the expression of CD68 was lower in Indian compared to European participants. The expression of the MSR1 gene was higher in European and Indian than African participants. Therefore, lower levels of expression of CD36 and MSR1 in African participants mirror a lower level of atherosclerotic disease observed in this population (15).
Scavenger receptor expression levels correlated with baseline fasting lipid profiles, ethnicity and age. Thus, CD36 expression levels correlated positively with LDL-C, CD68 expression and age, whilst CD68 expression correlated positively with triglycerides and European ethnicity. The expression of the MSR1 gene correlated positively with LDL-C, and negatively with both HDL-C and African ethnicity. The positive association of serum LDL levels with macrophage SR gene expression is a novel finding and is supported by a study showing that LDL upregulates the expression of macrophage SRs in a murine macrophage cell line (25). Lipoproteins, particularly minimally modified LDL and oxidized LDL can modulate signal transduction and gene expression in macrophages and other cells. Thus, LDL stimulates phosphoinositide turnover and elevates cytosolic calcium levels in vascular smooth muscle cells. Minimally modified LDL induces the expression of monocyte adhesion molecules, tissue factor, macrophage chemotactic protein-1 (MCP-1) and M-CSF in endothelial cells (25). Furthermore, high levels of plasma LDL has the ability to activate signal transduction and gene expression in macrophages (26), through stimulation of phosphoinositide turnover.
The association of serum lipid levels with macrophage SR expression that is described in the present study mirrors the effect of these lipid molecules on the risk of atherosclerosis. These data suggest that serum lipids may modulate atherosclerotic plaque formation by modifying the expression levels of scavenger receptors in circulating macrophages even before exposure to oxLDL.
Our findings were limited by the relatively small sample size however, we were still able to observe differences in SR levels across ethnicities and significant associations within the regression models. The other limitation is the analysis of associations between in vitro data i.e. SR expression, and in vivo data i.e. serum lipid levels. In performing these analyses we are assuming that lipid levels have an effect on macrophage SR expression that is not modified by monocyte isolation and cell culture conditions. Despite this limitation, it is interesting to note that the associations observed between serum lipid levels and in vitro macrophage SR expression are supported by other studies from the literature and are scientifically plausible.