Abstract 1311: Bone Marrow Angiotensin II Type 1 Receptor Augments Atherosclerosis by Promoting Monocyte/Macrophage Lineage Differentiation from Hematopoietic Stem Cells
[BACKGROUND] The angiotensin II (Ang II) type 1 (AT1) receptor is crucially involved in atherogenesis, but bone marrow (BM) AT1-mediated proatherogenic action remains undefined-
.[METHOD AND RESULT] BM-derived mononuclear cells (BM-MNCs) more abundantly express AT1 than VSMCs (2.2 fold) with similar affinities to Ang II. BM cells in 8-week-old apoE-deficient −/−) or wild-type (Agtr1+/+) cells. Four (apoE-KO) mice were replaced with AT1-deficient (Agtr1 weeks after the initiation of western diet and Ang II infusion (500ng/kg/min), atherosclerotic lesion area in aortic root was examined. ApoE-KO mice reconstituted with Agtr1−/− marrow (apoE-KO/BM-Agtr1−/−) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtr1+/+ mice (55%, P<0.05). The accumulation of macrophages was attenuated in apoE-KO/BM-Agtr1−/− mice (55%, P<0.05), concomitant with a decrease in the number of circulating Ly-6Chi monocytes (76%, P<0.01). The numbers of circulating CCR2+ and CX3CR1+ monocytes were also reduced in apoE-KO/BM-Agtr1−/− mice (87±16 vs 298±66; CCR2+ monocyte, 72±12 vs 550±119 cells/μl; CX3CR1+ monocyte, respectively, P<0.01). Furthermore, the number of macrophage progenitor cells defined by M-CSF stimulated macrophage colony-forming unit was markedly reduced by 82 % (p<0.01) in Agtr1−/−compared with Agtr1+/+ mice. We next examined the effect of BM-AT1 on the number of hematopoietic stem cells (HSCs), common myeloid progenitors (CMP), and granulocyte/macrophage progenitors (GMP) to determine at which point of the lineage pathway, BM-AT1 is involved. The number of HSCs did not differ between the two groups (3.6±0.8 vs 2.9±0.6 × 103cells/tibia, P=n.s.), whereas the numbers of CMP and GMP were much lower in apoE-KO/BM-Agtr1−/− mice (4.7±0.7 vs 10.2±1.4 ×103cells/tibia, 9.9±2.7 vs 20.2±2.8 × 103cells/tibia, respectively, P<0.05).
[CONCLUSION] BM-MNCs expressed the abundant densities of AT1, and AT1-mediated signals on BM-MNCs exaggerated atherosclerotic lesion development. BM-AT1 is closely implicated in the differentiation of HSCs into macrophage progenitors and the behavior of monocytes/macrophages, indicating that BM-AT1 could be a promising therapeutic target for the prevention of cardiovascular events.