Abstract 1337: The LDL Receptor is Required for the Inhibition of Atherosclerosis Provided by Low Levels of Apolipoprotein E in ApoE-Deficient Mice
Our laboratory has previously shown that very low levels of apoE (1–2% wild type levels) almost totally inhibit the development of atherosclerosis in apoE-deficient mice. Since these levels are too low to alter the lipoprotein profile in these mice, we hypothesized that the protection afforded by apoE is provided by its binding to and initiating signaling via a receptor. As apoE binds to all of the LDL receptor family members, we started our study by crossing our low expressing apoE mice onto an LDLr-deficient background. For mice fed a Western diet for 16 weeks, the total plasma cholesterols were not different between the two groups: apoE−/− LDLr−/− (n=13) 781 ± 124 mg/dl, apoE−/− adE LDLr−/− (mice carrying an adrenal specific mouse apoE transgene, n=8) 921 ± 174 mg/dl. FPLC lipoprotein profiles for the two groups were also the same. Similarly, the aorta cholesteryl ester (CE) deposition was not significantly different between the two groups: 126 ± 11 versus 151 ± ug/mg protein. In the mice fed a chow diet for 8 months there was no difference in total plasma cholesterols: apoE−/− LDLr−/− (n=14) 307 ± 18 mg/dl, apoE−/− adE LDLr−/− (n=12) 353 ± 27 mg/dl. Surprisingly, there was a slight but significant difference in the aorta cholesteryl ester deposition, with the low level apoE increasing the aorta CE: 40 ± 3 ug/mg protein with no apoE, 67 ± 12 ug/mg protein with low apoE, p = 0.0189. Since LDLr−/− mice (with wild type or higher concentrations of apoE) do not develop extensive atherosclerosis on a chow diet, we have crossed our “medium” expressing apoE transgenic lines (10–15ug/ml apoE versus 1–2 ug/ml apoE in low expressors) onto the LDLr−/− background to try to determine the apoE concentration critical for protection on this background. Other groups have shown that the absence of the LDL receptor in macrophages does not affect atherosclerosis, indicating that the effect we observe may be due to the presence of LDLr on either vascular endothelial or smooth muscle cells. These data demonstrate that the LDLr is essential for the atheroprotection provided by low level apoE.