Abstract 15514: Lymphoid but Not Phagocytic Deficiency in G Protein-Coupled Receptor Kinase 2 Decreases Atherosclerotic Plaque Formation in LDLr−/− Mice
Background: Migration of leukocytes towards sites of inflammation, such as atherosclerotic lesions, is guided through chemokines, which interact with G protein-coupled receptors (GPCR) on leukocytes. This process is controlled by phosphorylation of these receptors through GPCR kinases (GRK). GRKs dampen the response of the chemokine signaling and as such regulate the migration of leukocytes towards the lesion. Given the major role of CCR1, CCR2, and CCR5 in atherogenesis, we focussed on GRK2 in this study, and assessed the role of GRK2 deficiency in haematopoietic cells on the atherogenic response in LDLr−/− mice.
Methods & Results: A bone marrow transplant was performed to generate LDLr−/− chimeras with a partial GRK2 deficiency in the haematopoietic lineage. GRK2+/− chimeras developed smaller lesions compared with wild-type controls (WT 585.0 ± 56.4x103 μm2 vs GRK2+/− 403.0 ± 43.8x103 μm2; p=0.017). Moreover, lesions in the GRK2+/− mice also had a 78% reduction in necrotic core size (p<0.00001) and an increased number of intimal macrophages (WT 15.3 ± 2.4% vs GRK2+/− 32.3 ± 2.9% p<0.001). Migration assays revealed reduced chemokinetic capacity of WT versus GRK2+/− monocytes/macrophages. As the phenotype pointed to a key role of macrophage GRK2 in atherosclerosis we sought to investigate the effect of conditional macrophage GRK2 deficiency on atherosclerosis using LysM Cre GRK2f/f donor mice. Unlike the GRK2+/− chimeras the LysM Cre GRK2f/f had unaltered levels of myeloid subsets, yet B-cells and DCs in blood, spleen and lymph nodes were elevated (p<0.01). After induction of a peritonitis there was even a decrease in monocyte and granulocyte influx compared to WT. Surprisingly, histological analysis showed that GRK2 deficiency in LysM+ cells did not have any effect on total lesion area, necrotic core and macrophage influx, identifying non-myeloid GRK2 as decisive in atherosclerosis.
Conclusions: Partial disruption of GRK2 in haematopoietic cells results in attenuated plaque development and lesions that do not progress beyond the fatty streak stage. This effect is not directly attributable to GRK2 activity in macrophages, unveiling a key role for T-cells or dendritic cells in GRK2 dependent modulation of macrophage homeostasis and atherosclerosis.
- © 2010 by American Heart Association, Inc.