Abstract 3609: Both leukocyte and non-leukocyte Blt1 contribute to atherogenesis
5-lipoxygenase and its product LTB4 are highly expressed in human vascular disease. LTB4 signals primarily through its receptor Blt1, which has been thought to be expressed only on leukocytes. We have demonstrated a greater than two-fold reduction in atherosclerotic lesion formation in Apoe−/−/Blt1−/− mice as compared to Apoe−/− controls. Surprisingly, there was a striking effect of Blt1 receptor deletion on vascular smooth muscle cell accumulation in atherosclerotic lesions, suggesting a new role for Blt1 in atherogenesis. Here we tested the hypothesis that Blt1 expression on non-leukocytes contributes directly to atherogenesis using bone marrow transplantation (BMT) studies. Apoe−/−/Blt1+/+ and Apoe−/−/Blt1−/− mice were lethally irradiated and repopulated with bone marrow-derived cells of either genotype. After 6 weeks, mice were infused with Angiotensin II (1000 ng/kg/min) to accelerate atherosclerosis formation. Flow cytometric analysis was used to ensure successful BMT (CD4+ cells: 80 ± 6%, CD8+ cells: 85 ± 4%, CD11b+ cells: 92 ± 1%, B220+ cells: 99 ± 0.4%, and Gr1+ cells: 82 ± 2%). After 4 weeks of infusion, mice were sacrificed for blood collection and en face atherosclerotic morphometric analyses. As expected, Apoe−/− mice reconstituted with Apoe−/−bone marrow developed robust atherosclerosis. In contrast, chimeric mice in which Blt1-deficient mice were bone marrow donors or recipients had striking reductions in atherosclerotic lesion formation as compared to Apoe−/− mice (Apoe−/− → Apoe−/−: 5.6±1.7%, n=4; versus Blt1−/−→Apoe−/−: 1.4±0.7%, n=3, 75% reduction, p=0.01; Apoe−/−→Blt1−/−: 1.9±0.6%, n=6, 66% reduction, p=0.008; and Blt1−/−→ Blt1−/−: 2±0.6%, n=6, 64% reduction, p=0.01). Interestingly, there was no synergistic effect of Blt1 deletion in both the resident and the hematopoietic cell population when compared to Blt1 deficiency in either leukocyte or resident component alone (p=0.8). Thus, Blt1 receptor on both bone marrow-derived and resident cells contributes to the extent of atherosclerosis. These findings are clinically relevant because small-molecule antagonists of Blt1 that are under development could target multiple cellular constituents of plaques.
This research has received full or partial funding support from the American Heart Association, AHA National Center.