6 atherosclerosis by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1aR. They also mentioned that Ang II infusion increased the number of smooth muscle progenitor cells, which are peripheral blood cells that turn to α-smooth muscle actin-positive cells after culture in the presence of PDGF-BB. These smooth muscle- like cells expressed abundant matrix metalloproteinase-9 (MMP-9), which substantially contribute to destabilization of atherosclerotic plaques [21]. Their results suggested that blockade of AT1R not only in vascular cells but also in BM could be an important strategy to prevent atheroscle- rosis. In a previous study by Cassis et al. [120] it has been shown that, bone marrow recipient AT1a receptors are required to initiate Ang II-induced atherosclerosis in hypercholesterolemic mice in which bone marrow transplan- tation studies were performed. They have concluded that AT1a receptors expressed on inﬁltrating cells exert modest regulation of Ang II-induced atherosclerosis. Moreover the existence of this receptor in resident tissue is necessary for the initiation of Ang II-induced atherosclerosis and abdominal aortic aneurysms. An other study by Tsubakimoto et al. [121], the Ang II regulated diﬀerentiation/proliferation of monocyte-lineage cells to exert proatherogenic actions was clearly deﬁned. In this study the authors generated BM chimeric apoE negative mice repopulated with AT1- deﬁcient (Agtr1−/−) or wild-type (Agtr1+/+)) BM cells. The atherosclerotic development was signiﬁcantly reduced in apoE−/−/BM-Agtr1−/− mice compared with apoE−/−/BM- Agtr1+/+ mice, accompanied by decreased numbers of BM granulocyte/macrophage progenitors and peripheral blood monocytes. And ﬁnally they have been proposed that Ang II controls the expression of c-Fms in HSCs and monocyte- lineage cells through BM stromal cell derived TNF-alpha to promote M-CSF–induced diﬀerentiation/proliferation of monocyte-lineage cells and contributes to the proatherogenic action [121]. In contrary to the studies demonstrating that [21, 122] blockade of AT1 receptor in BM cells might have inhibitory eﬀects on atherosclerosis, little or no changes of atheroscle- rosis in LDL receptor knockout mice by transplantation with BM from AT1a receptor knockout mice are also reported [120, 123]. These reports suggest the ameliorative function of AT1 receptor blockade in vascular cells for the AT1 receptor blocker- (ARB-) mediated atherosclerosis inhibition. In conjunction with the latter reports, the study by Kato et al. [124] also demonstrates that the beneﬁcial eﬀects of ARB in end-organ injuries are due to the blockade of AT1 receptor expressed in the end organs, but not in bone-marrow-derived cells. They proposed that distinct results observed in the kidney injury and atherosclerosis is possibly from the diﬀerences in the pathogenesis of mouse models. Moreover they have speculated that depend- ing upon the tissues and model systems examined, AT1 receptor function in BMDCs may have diﬀerential action points. Taken as a whole, the hematopoietic BM RAS, as well as local vasculature RAS, plays a crucial role in the initiation and progression of atherosclerosis, thereby contributing to development of cardiovascular diseases. Cardiology Research and Practice 5. Future Therapeutic Perspectives Endothelial dysfunction, cellular proliferation, and pro- grammed inﬂammation triggered by RAS provide a clue to a novel understanding of the pathological hallmark of atherosclerosis, and may be important in developing new antiatherosclerotic strategies. AT1aR expressed on BM- derived cells plays a crucial role in the pathogenesis of atherosclerosis by accelerating BM-derived inﬂammatory cell inﬁltration in the vessel wall. For that reason, AT1R blockade not only in vascular cells but also in BM could help to prevent progression and destabilization of atherosclerotic plaques [21, 26, 117, 119, 125]. Pharmacological therapeutic strategies must focus on the distribution and the density of angiotensin receptors, gene expression, and proteomics along hematopoietic BM structures. Future therapeutic interventions would interfere with the pathobiological acti- vation of the local hematopoietic BM in a variety of diseases, particularly atherosclerosis, to elucidate the importance of the system from an actual clinical point of view. In summary, a large number of studies have shown that RAS has a central role in the initiation and progression of atherosclerosis, as outlined in this paper. Ang II may com- promise the structural integrality of the endothelial barrier by induction of endothelial cell apoptosis. Inﬂammatory reaction in the vascular intimal layer involving macrophages and T lymphocytes by RAS-induced oxidative stress and hyperthrombotic state results in oxidative lipoprotein mod- iﬁcation, smooth muscle cell migration from the media into the intima, proliferation, and transformation from a contractile to a synthetic phenotype. While the earlier stages may remain subclinical, this stage of the atherosclerotic process leads to a signiﬁcant reduction in the vessel lumen. AT1aR expressed not only on vascular cells but also on BM-derived cells plays a role in the atherosclerotic plaque pathogenesis, at least partially by accelerating inﬁltration of BM-derived inﬂammatory cells in the vessel wall. Under- standing the diversity of intracellular Ang II synthesis pathways may help in developing therapeutic interventions, and blockade of AT1R not only in vascular cells but also in BM could be an important strategy to prevent progression and destabilization of atherosclerotic plaques. Acknowledgment The authors would like to thank to Dr. Sureyya Altunay, for providing them an excellent illustration of local hematopoi- etic bone marrow RAS in association with cardiac RAS. References [1] C. M. Ferrario and W. B. Strawn, “Role of the renin- angiotensin-aldosterone system and proinﬂammatory medi- ators in cardiovascular disease,” American Journal of Cardiol- ogy, vol. 98, no. 1, pp. 121–128, 2006. [2] S. Oparil and E. Haber, “The renin-angiotensin system (ﬁrst of two parts),” New England Journal of Medicine, vol. 291, no. 9, pp. 389–401, 1974.