Whole Body And Hematopoietic Sortilin Deficiency Reduces Atherosclerosis In Mice Independent Of Effects On Ldl Cholesterol

Background: Genetic variants on chromosome 1p13 at the SORT1 locus are genome-wide significantly associated with both LDL cholesterol as well as with myocardial infarction (MI). Sortilin, encoded by the SORT1 gene, traffics to both the Golgi as well as the plasma membrane, where it binds ligands and transports them to the lysosome. Our lab recently showed that sortilin is a high affinity receptor for LDL, and genetic manipulation of sortilin expression in the liver influences LDL-C levels. Sortilin is also expressed in macrophages but little is know about its function in this cell type or its relationship to atherosclerosis. Results: Sortilin deficient mice were crossed to atherosclerosis-prone Apobec-/-; human ApoB Tg mice. On this model, plasma total and LDL-C levels were not different in the sortilin deficient vs the wild-type mice. Unexpectedly, aortic atherosclerosis measured en face was reduced by 90% (n=10 per group; P = 5.3 E-7). To determine whether hematopoetic sortilin contributed to this effect, we performed bone marrow transplantation studies from done Sort1-/-; Ldlr -/- or Ldlr -/- mice into atherosclerosis-prone LDLR-/- mice and fed a western diet for 18 weeks (n=11-12/group). Plasma cholesterol was not different in the two groups of mice. Aortic atherosclerosis was reduced by 50% (P < 1E-5) in mice lacking sortilin. Sortilin deficient bone marrow derived macrophages had significantly reduced LDL uptake by ~39% (P = 0.02). In the presence of a actin polymerization inhibitor cytochalasin D, sortilin deficiency further reduces LDL uptake by 38% (P = 0.03) Conclusion: Whole body and hematopoetic sortilin deficiency reduce atherosclerosis in mice. Sortilin deficient macrophages have reduced uptake of native LDL, potentially at least partially accounting for the reduced atherosclerosis. Sortilin deficient macrophages have reduced uptake of native LDL, which is not abrogated by inhibition of macropinocytosis. Our data are consistent with a model in which sortilin deficiency in macrophages protects against atherosclerosis by eliminating an uptake pathway for LDL into macrophages and suggests that sortilin mediated LDL uptake is an important contributor to atherosclerosis development.