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Int. J. Mol. Sci. 2018, 19(9), 2621; https://doi.org/10.3390/ijms19092621

Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability

1
Division of Angiology, Heart and Vessel Department, Lausanne University Hospital, 1011 Lausanne, Switzerland
2
Service and Central Laboratory of Hematology, LABORATORY and Oncology DepartmentS, Lausanne University Hospital, 1011 Lausanne, Switzerland
*
Author to whom correspondence should be addressed.
Received: 2 August 2018 / Revised: 24 August 2018 / Accepted: 31 August 2018 / Published: 4 September 2018
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis)
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Abstract

Angiotensin (Ang) II triggers vulnerable atherosclerotic plaque development. Bone marrow (BM)-derived cells are key players in atherogenesis but whether Ang II induces plaque vulnerability directly through Ang II type 1 receptor (AT1R) activation on these cells remains to be clarified. In the present study, we investigated whether a lack of AT1R on BM-derived cells might affect Ang II-mediated vulnerable plaque development. The 2-kidney, 1-clip (2K1C) model (Ang II-dependent mouse model of advanced atherosclerosis and vulnerable plaques) was generated in ApoE−/− mice transplanted with AT1aR−/− or AT1aR+/+ BM. Plasma cholesterol as well as hepatic mRNA expression levels of genes involved in cholesterol metabolism were significantly lower in 2K1C mice transplanted with AT1aR−/− BM than in controls. Atherosclerotic lesions were significantly smaller in AT1aR−/− BM 2K1C mice (−79% in the aortic sinus and −71% in whole aorta compared to controls). Plaques from AT1aR−/− BM 2K1C mice exhibited reduced lipid core/fibrous cap and macrophage/smooth muscle cells ratios (−82% and −88%, respectively), and increased collagen content (+70%), indicating a more stable phenotype. Moreover, aortic mRNA levels of pro-inflammatory cytokines IL-12p35, IL-1β, and TNF-α were significantly reduced in AT1aR−/− BM 2K1C mice. No significant differences in either the number of circulating Ly6Chigh inflammatory monocytes and Ly6Clow resident anti-inflammatory monocyte subsets, or in mRNA levels of aortic M1 or M2 macrophage markers were observed between the two groups. No significant differences were observed in splenic mRNA levels of T cell subsets (Th1, Th2, Th17 and Treg) markers between the two groups. In conclusion, direct AT1R activation by Ang II on BM-derived cells promotes hepatic mRNA expression of cholesterol-metabolism-related genes and vascular mRNA expression of pro-inflammatory cytokines that may lead to plaque instability. View Full-Text
Keywords: atherosclerosis; vulnerable plaque; Angiotensin II; inflammation; 2-kidney, 1-clip ApoE−/− mice; bone marrow transplantation atherosclerosis; vulnerable plaque; Angiotensin II; inflammation; 2-kidney, 1-clip ApoE−/− mice; bone marrow transplantation
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Pellegrin, M.; Bouzourène, K.; Aubert, J.-F.; Nahimana, A.; Duchosal, M.A.; Mazzolai, L. Activation of Bone Marrow-Derived Cells Angiotensin (Ang) II Type 1 Receptor by Ang II Promotes Atherosclerotic Plaque Vulnerability. Int. J. Mol. Sci. 2018, 19, 2621.

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