Abstract 1148: Bone Marrow Angiotensin II Type 1 Receptor Accelerated the Development of Atherosclerosis by Regulating Differentiation of Macrophage Progenitors and Macrophage Functions
[BACKGROUND] Bone marrow (BM) cells and angiotensin II (Ang II) are crucially involved in atherosclerosis, whereas the mechanism for BM- AT1-mediated proatherogenic action remains poorly defined.
[METHOD AND RESULT] BM-derived mononuclear cells (BM-MNCs) more abundantly express AT1 than VSMCs (2.2 fold higher) with similar affinities to Ang II. Total BM cells from AT1 receptor-deficient (AT1-KO) or wild type (WT) mice were transplanted into BM-ablated apoE-KO mice. Four weeks after the initiation of western diet and Ang II infusion (500ng/kg/min), atherosclerotic lesion area in aortic root was examined. BM-AT1/apoE-DKO mice showed significant reduction of atherosclerotic lesion area compared with apoE-KO mice (0.31 ± 0.04 vs 0.71 ± 0.20 mm2, p<0.05). The accumulation of monocyte/macrophage and T lymphocyte was also reduced in BM-AT1/apoE-DKO mice (55 % and 87 %, respectively, p<0.05). Circulating endothelial progenitor cells (EPC) defined by Flk-1+/Sca-1+ markers, did not show difference between two groups (1.1 ± 0.2 vs 1.6 ± 0.4 %, p=n.s.). In contrast, the number of macrophage progenitor cells defined by M-CSF stimulated macrophage colony-forming unit was markedly reduced by 82 % (p<0.01) in AT1-KO compared with WT. Consistent with this finding, the number of circulating monocyte (CD11b+ cells) at both baseline and after Ang II infusion showed much lower in BM-AT1/apoE-DKO mice than apoE-KO mice (431 ± 77 vs 1360 ± 147 cells/μl, baseline; p<0.0001, 871 ± 207 vs 1074 ± 292 cells/μl, after Ang II infusion; p<0.05). Circulating monocytes from BM-AT1/apoE-DKO mice showed lower CCR2 expression than apoE-KO mice (130 ± 11 vs 212 ± 13 MFI, p=0.02), accompanied with the attenuation of MCP-1-induced migration activity (21 ± 8 vs 49 ± 5 cells/mm2, p=0.04). Foam cell formation in peritoneal macrophages from AT1-KO mice was also reduced compared with WT mice (2.3 ± 0.6 vs 4.8 ± 0.1 %, p=0.01).
[CONCLUSION] BM-MNCs expressed the abundant densities of AT1, and AT1-mediated signals on BM-MNCs exaggerated atherosclerotic lesion development. BM-AT1 regulates the differentiation and/or self-renewal activity of macrophage progenitors and macrophage functions, suggesting that BM-AT1 could be a promising therapeutic target for the prevention of cardiovascular events.