title: Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis.
abstract: Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages. In endothelial cells, conversely, NO is strongly anti-atherogenic. However, until now, the role of Arg1 in atherosclerosis is largely unknown. The aim of this study is to specifically investigate the effect of Arg1 deletion in hematopoietic cells on atherosclerosis susceptibility.
  
  
  
  Ldlr KO mice were transplanted with Arg1flox/flox;Tie2-Cre (Arg1 KO) bone marrow (BM) or wildtype (WT) BM. After 8 weeks of recovery on chow diet, recipients mice were fed a Western-Type Diet (WTD) for 10 weeks to induce atherosclerosis.
  
  
  
  After 10-week WTD challenge, blood leukocyte counts were decreased by 25% (p < 0.001), and spleen leukocytes were decreased by 35% (p = 0.05) in Ldlr KO mice transplanted with Arg1 KO BM compared to mice transplanted with WT BM. The decrease in leukocytes was due to lower B lymphocyte counts. However, oxLDL-specific antibodies were increased in plasma of Ldlr KO mice transplanted with Arg1 KO BM compared to WT BM transplanted controls, whereas oxLDL-specific IgM was not affected. On the other hand, peritoneal foam cells in Arg1 KO BM recipients were increased 3-fold (p < 0.001) compared to WT BM recipients. No change in blood cholesterol was found. Despite changes in leukocyte counts and macrophage foam cell formation, we did not observe differences in atherosclerotic plaque size or plaque macrophage content in the aortic root. Surprisingly, there was also no difference in plaque collagen content, indicating that absence of macrophage Arg1 function does not reduce plaque stability.
  
  
  
  Deletion of Arg1 in hematopoietic cells adversely affects blood leukocyte counts and increases foam cell formation. However, no effects on atherosclerosis could be demonstrated, indicating that hematopoietic Arg1 function is not a decisive factor in atherosclerotic plaque formation.
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Electronic address: b.ren@lacdr.leidenuniv.nl.
authors.forename: Baoyan
authors.initials: B
authors.lastname: Ren
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Van Kampen
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.affiliation: Manchester Immunology Group, Faculty of Life Sciences, The University of Manchester, Manchester, UK.
authors.forename: Sheena M
authors.initials: SM
authors.lastname: Cruickshank
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D007964:Leukocytosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: B-cells; Bone marrow transplantation; Inos; Nitric oxide; Tie2Cre; oxLDL