BubR1 Insufficiency Results in Decreased Macrophage Proliferation and Attenuated Atherogenesis in Apolipoprotein E‐Deficient Mice

Background Budding uninhibited by benzimidazole‐related 1 (BubR1), a cell cycle–related protein, is an essential component of the spindle checkpoint that regulates cell division. BubR1 insufficiency causes early aging‐associated vascular phenotypes. We generated low‐BubR1‐expressing mutant (BubR1 L/L) and apolipoprotein E‐deficient (ApoE −/−) mice (BubR1 L/L ‐ApoE −/− mice) to investigate the effects of BubR1 on atherosclerosis. Methods and Results Eight‐week‐old male BubR1 L/L ‐ApoE −/− mice and age‐matched ApoE −/− mice were used in this study. Atherosclerotic lesion development after being fed a high‐cholesterol diet for 12 weeks was inhibited in BubR1 L/L ‐ApoE −/− mice compared with ApoE −/− mice, and was accompanied by decreased accumulation of macrophages. To address the relative contribution of BubR1 on bone marrow–derived cells compared with non‐bone marrow–derived cells, we performed bone marrow transplantation in ApoE −/− and BubR1 L/L ‐ApoE −/− mice. Decreased BubR1 in bone marrow cells and non‐bone marrow–derived cells decreased the atherosclerotic burden. In vitro assays indicated that decreased BubR1 expression impaired proliferation, but not migration, of bone marrow–derived macrophages. Conclusions BubR1 may represent a promising new target for regulating atherosclerosis.

[1]  Y. Maehara,et al.  BubR1 Insufficiency Inhibits Neointimal Hyperplasia Through Impaired Vascular Smooth Muscle Cell Proliferation in Mice , 2015, Arteriosclerosis, thrombosis, and vascular biology.

[2]  F. Gonzalez,et al.  Bisphenol A Increases Atherosclerosis in Pregnane X Receptor‐Humanized ApoE Deficient Mice , 2014, Journal of the American Heart Association.

[3]  K. Sunagawa,et al.  Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes , 2014, Circulation.

[4]  Y. Momiyama,et al.  Inflammation, Atherosclerosis and Coronary Artery Disease , 2014, Clinical Medicine Insights. Cardiology.

[5]  P. Libby,et al.  Immune effector mechanisms implicated in atherosclerosis: from mice to humans. , 2013, Immunity.

[6]  P. Libby,et al.  Local proliferation dominates lesional macrophage accumulation in atherosclerosis , 2013, Nature Medicine.

[7]  C. Weber,et al.  Atherosclerosis: current pathogenesis and therapeutic options , 2011, Nature Medicine.

[8]  L. Lanier,et al.  DAP12 Is Required for Macrophage Recruitment to the Lung in Response to Cigarette Smoke and Chemotaxis toward CCL2 , 2010, The Journal of Immunology.

[9]  A. Tall,et al.  Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice. , 2009, The Journal of clinical investigation.

[10]  B. Porse,et al.  Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. , 2008, CSH protocols.

[11]  D. Welsh,et al.  The Lineage−c‐Kit+Sca‐1+ Cell Response to Escherichia coli Bacteremia in Balb/c Mice , 2008, Stem cells.

[12]  D. Baker,et al.  Aging-Associated Vascular Phenotype in Mutant Mice With Low Levels of BubR1 , 2007, Stroke.

[13]  Y. Pak,et al.  HMG-CoA Reductase Inhibition Reduces Monocyte CC Chemokine Receptor 2 Expression and Monocyte Chemoattractant Protein-1–Mediated Monocyte Recruitment In Vivo , 2005, Circulation.

[14]  Hiroshi Nakamura,et al.  Dual roles for NF-kappaB activation in osteoblastic cells by serum deprivation: osteoblastic apoptosis and cell-cycle arrest. , 2004, Bone.

[15]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[16]  A. Togari,et al.  Activation of Caspases Is Required for Osteoblastic Differentiation* , 2003, Journal of Biological Chemistry.

[17]  P. Libby.  Inflammation in atherosclerosis , 2002, Nature.

[18]  Hongtao Yu,et al.  Regulation of APC-Cdc20 by the spindle checkpoint. , 2002, Current opinion in cell biology.

[19]  Hiroshi Nakamura,et al.  Differential expression of the Fas-Fas ligand system on cytokine-induced apoptotic cell death in mouse osteoblastic cells. , 2002, Archives of oral biology.

[20]  K. Mori,et al.  Nitric Oxide-induced Apoptosis in RAW 264.7 Macrophages Is Mediated by Endoplasmic Reticulum Stress Pathway Involving ATF6 and CHOP* , 2002, The Journal of Biological Chemistry.

[21]  C. Damsky,et al.  Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages. , 1999, Journal of cell science.

[22]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[23]  A. Newby,et al.  Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. , 1999, Cardiovascular research.

[24]  R. Ross,et al.  Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[25]  Marc W. Kirschner,et al.  How Proteolysis Drives the Cell Cycle , 1996, Science.

[26]  R. Williams,et al.  Quantitative assessment of atherosclerotic lesions in mice. , 1987, Atherosclerosis.

[27]  S. Schwartz,et al.  Kinetics of Atherosclerosis: A Stem Cell Model , 1985, Annals of the New York Academy of Sciences.

[28]  M. Reidy,et al.  Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. , 1983, Laboratory investigation; a journal of technical methods and pathology.

[29]  J. Austyn,et al.  Expression of the macrophage-specific antigen F4/80 during differentiation of mouse bone marrow cells in culture , 1981, The Journal of experimental medicine.

[30]  Aldons J. Lusis,et al.  Atherosclerosis : Vascular biology , 2000 .

[31]  R. Ross,et al.  ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.