Mi Wang1, Manikandan Subramanian, Sandra Abramowicz, Andrew J Murphy, Ayelet Gonen, Joseph Witztum, Carrie Welch, Ira Tabas, Marit Westerterp, Alan R Tall. 1. From the Division of Molecular Medicine, Department of Medicine (M. Wang, M.S., S.A., A.J.M., C.W., I.T., M. Westerterp, A.R.T.) and Department of Pharmacology (M. Wang), Columbia University, New York, NY; Department of Medicine, University of California San Diego, La Jolla (A.G., J.W.); and Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (M. Westerterp).
Abstract
OBJECTIVE: Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE(-/-) mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor (CBS) on HSPCs. ApoE(-/-) mice also display increased granulocyte macrophage colony-stimulating factor-dependent monocyte production in the spleen. We investigated the role of the CBS in cholesterol-driven HSPC expansion, monocytosis, and atherosclerosis. APPROACH AND RESULTS: Ldlr(-/-) mice were transplanted with ApoE(-/-)Cbs(-/-) or ApoE(-/-) BM followed by Western-type diet feeding. Compared with ApoE(-/-) BM-transplanted controls, ApoE(-/-)Cbs(-/-) BM-transplanted mice had reduced BM and splenic HSPC proliferation, fewer blood monocytes and neutrophils, and reduced macrophage content and area of early atherosclerotic lesions. More advanced lesions showed diminished macrophage and collagen content; however, lesion size was unchanged, reflecting an increase in necrotic core area, associated with a marked decrease in Abcg1 expression and increased macrophage apoptosis. Compared with wild-type mice, Western-type diet-fed ApoE(-/-) mice showed increased CBS expression on granulocyte macrophage colony-stimulating factor-producing innate response activator B cells and expansion of this population. ApoE(-/-)Cbs(-/-) BM-transplanted Ldlr(-/-) mice showed a marked decrease in innate response activator B cells compared with ApoE(-/-) BM-transplanted Ldlr(-/-) controls. CONCLUSIONS: Increased levels of CBS on HSPCs and splenic innate response activator B cells lead to expansion of these populations in ApoE(-/-) BM-transplanted Ldlr(-/-) mice, contributing to monocytosis and increased lesional macrophage content. However, in more advanced lesions, the CBS also has a role in atherosclerotic plaque stabilization.
OBJECTIVE:Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE(-/-) mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor (CBS) on HSPCs. ApoE(-/-) mice also display increased granulocyte macrophage colony-stimulating factor-dependent monocyte production in the spleen. We investigated the role of the CBS in cholesterol-driven HSPC expansion, monocytosis, and atherosclerosis. APPROACH AND RESULTS:Ldlr(-/-) mice were transplanted with ApoE(-/-)Cbs(-/-) or ApoE(-/-) BM followed by Western-type diet feeding. Compared with ApoE(-/-) BM-transplanted controls, ApoE(-/-)Cbs(-/-) BM-transplanted mice had reduced BM and splenic HSPC proliferation, fewer blood monocytes and neutrophils, and reduced macrophage content and area of early atherosclerotic lesions. More advanced lesions showed diminished macrophage and collagen content; however, lesion size was unchanged, reflecting an increase in necrotic core area, associated with a marked decrease in Abcg1 expression and increased macrophage apoptosis. Compared with wild-type mice, Western-type diet-fed ApoE(-/-) mice showed increased CBS expression on granulocyte macrophage colony-stimulating factor-producing innate response activator B cells and expansion of this population. ApoE(-/-)Cbs(-/-) BM-transplanted Ldlr(-/-) mice showed a marked decrease in innate response activator B cells compared with ApoE(-/-) BM-transplanted Ldlr(-/-) controls. CONCLUSIONS: Increased levels of CBS on HSPCs and splenic innate response activator B cells lead to expansion of these populations in ApoE(-/-) BM-transplanted Ldlr(-/-) mice, contributing to monocytosis and increased lesional macrophage content. However, in more advanced lesions, the CBS also has a role in atherosclerotic plaque stabilization.
Authors: N Itoh; S Yonehara; J Schreurs; D M Gorman; K Maruyama; A Ishii; I Yahara; K Arai; A Miyajima Journal: Science Date: 1990-01-19 Impact factor: 47.728
Authors: U Testa; C Fossati; P Samoggia; R Masciulli; G Mariani; H J Hassan; N M Sposi; R Guerriero; V Rosato; M Gabbianelli; E Pelosi; M Valtieri; C Peschle Journal: Blood Date: 1996-11-01 Impact factor: 22.113
Authors: Wei Wang; Yang Tang; Ying Wang; Liana Tascau; Joanna Balcerek; Wei Tong; Ross L Levine; Carrie Welch; Alan R Tall; Nan Wang Journal: Circ Res Date: 2016-07-18 Impact factor: 17.367
Authors: Vincent Sarrazy; Manon Viaud; Marit Westerterp; Stoyan Ivanov; Sophie Giorgetti-Peraldi; Rodolphe Guinamard; Emmanuel L Gautier; Edward B Thorp; Darryl C De Vivo; Laurent Yvan-Charvet Journal: Circ Res Date: 2016-02-29 Impact factor: 17.367