We have previously described 2 strains of New Zealand White rabbits with a high (HAR) or low (LAR) atherosclerotic response to hypercholesterolemia. In the present study, we focused on class A scavenger receptor (SR-A) activity and ApoE expression in macrophages from both rabbit strains. These parameters play a crucial role in maintaining cholesterol homeostasis in the arterial wall and may be involved in the development of atherosclerosis. SR activity, as measured by uptake of DiI-labeled acetylated LDL, was significantly higher in macrophages from LAR rabbits (2177+/-253 ng/mg cell protein) than in macrophages from HAR rabbits (1153+/-200 ng/mg cell protein). The higher SR activity was caused by a greater number of SRs (apparent Vmax, 4100 ng/mg in LAR and 1980 ng/mg in HAR rabbits). The high SR activity in macrophages from LAR rabbits was associated with a significantly higher expression of SR-A mRNA compared with macrophages from HAR rabbits. However, the latter finding could not be explained by differences in the activity of transcription factor-activating protein 1 (AP-1), which was comparable in macrophages from both strains of rabbits. Because under certain circumstances SR-A mRNA expression is regulated in parallel with ApoE expression, we also evaluated this parameter. Although ApoE mRNA was 74% higher in macrophages from LAR rabbits, the difference did not reach statistical significance. In conclusion, the increased expression of SR-A in macrophages in the presence of adequate amounts of ApoE may play a role in attenuating atherosclerosis in LAR rabbits.