Abstract 661: Targeting Sortilin in Immune Cells Reduces Atherosclerosis
Targeting sortilin in immune cells reduces atherosclerosis.
Background: SNPs at 1p13.3 have been strongly associated with myocardial infarction and plasma cholesterol levels in genome-wide association studies. This locus covers 3 genes; SORT1, CELSR2 and PSRC1. Previous studies on sortilin in cardiovascular disease have focused on sortilins role in hepatic lipoprotein metabolism. In the present study, we demonstrate that sortilin also modulates atherogenesis independent of its effect on lipoprotein metabolism.
Methods and results: The effect of sortilin deficiency on atherosclerosis was studied in Apoe-/- mice. Absence of sortilin (Sort1-/-) did not influence plasma cholesterol levels or the distribution between lipoprotein fractions, yet significantly reduced development of atherosclerosis after both 6 and 18 weeks of Western diet. To examine the possible mechanism we performed studies on murine bone marrow-derived macrophages (BMM) and th1-cells. Loss of sortilin did not impact foam-cell formation or cell activation, but specifically reduced the secretion of interleukin-6 (Il-6) and interferon-gamma (IFN-) from macrophages and th1 cells, respectively. Further, surface plasmon resonance analysis demonstrated that sortilin binds these two cytokines with high affinity. These results suggest that sortilin is involved in regulation of Il-6 and IFN- secretion and indicates that sortilin in immune cells may influence atherosclerosis.
To test this hypothesis, 8 weeks old Apoe-/- were lethally irradiated and rescued with age- and sex-matched bone marrow from Sort1+/+Apoe-/- or Sort1-/-Apoe-/- donor mice. Mice with a sortilin deficient bone marrow transplant had reduced development atherosclerosis compared to mice with a Sort1+/+ transplant. Although these mice had normal numbers of circulating immune cells, they had reduced levels of circulating tumor necrosis factor-α and Il-6 in plasma, suggesting that absence of sortilin attenuates the inflammatory response.
Conclusions: We conclude that targeting sortilin in immune cells reduces atherosclerosis by attenuation of the inflammatory response.
Author Disclosures: M.B. Mortensen: None. M. Kjolby: None. S. Gunnersen: None. J.V. Larsen: None. J. Palmfeldt: None. E. Falk: None. A. Nykjær: None. J.F. Bentzon: None.
- © 2014 by American Heart Association, Inc.