Abstract 19004: Sr-bi Deficiency is Associated with Dendritic Cell Retention in Arterial Atherosclerotic Plagues and Impaired Atherosclerotic Regression in Apoe-r61 Hypomorphic Mice
A deficiency in SR-BI, a major HDL receptor, results in accelerated arterial plaque development in ApoE-R61 hypomorphic mice, however the effect of a lack of SR-BI on atherosclerotic plaque regression is unknown. In SR-BI-knockout/ApoE hypomorphic (KO-H ) mice fed a high fat diet, aortic atherosclerosis developed much faster than in the SR-BI+/+ ApoE hypomorphic (control) mice. When these mice were switched from the atherogenic diet back to a normal diet, atherosclerotic plaques regressed over the course of 11 weeks in the control mice, but not in KO-H mice, in which the plaques continued to develop. Dendritic cells (DC's) have been found to be involved in atherosclerosis development and regression. Immunohistofluorescence analysis revealed a large number of CD11c-positive DC’s which persisted within atherosclerotic lesions of KO-H mice, even 11 weeks after the diet switching. These CD11c-positive cells exhibited apparently attenuated expression of CCR7, a major chemoattractant receptor in DCs. To determine if SR-BI in macrophages or DC’s themselves might be required for plaque regression, bone marrow (BM) was transplanted from either KO-H or control donors into irradiated ApoE-hypomorphic recipients. Plaque regression was decreased in the mice transplanted with BM from KO-H donors, confirming a role for SR-BI in BM-derived cells in plaque regression. In cultured human DC's derived from THP-1 cells, HDL dose-dependently stimulated migration. HDL-stimulated migration of DC's was abolished by a SR-BI blocking antibody, PI 3-kinase inhibitors or using BM-derived DC's from SR-BI or PDZK1 KO mice, suggesting the involvement of an HDL-triggered PI3K signaling pathway emanating from SR-BI and its cytosolic adaptor protein PDZK1. Cholesterol loading of DCs impaired migration in response to HDL or CCL19, a ligand for CCR7; this was reversed by overnight incubation with HDL. Furthermore, incubation with HDL for 24 h induced a remarkable increase in expression of CCR7 and SR-BI in DC's. Taken together, the results suggest that SR-BI may mediate the migration of DC's facilitated by HDL, and is required for atherosclerotic plaque regression.
- © 2012 by American Heart Association, Inc.