title: Angiotensin-converting enzyme is required for normal myelopoiesis.
abstract: Inhibition of angiotensin-converting enzyme (ACE) induces anemia in humans and mice, but it is unclear whether ACE is involved in other aspects of hematopoiesis. Here, we systemically evaluated ACE-knockout (KO) mice and found myelopoietic abnormalities characterized by increased bone marrow myeloblasts and myelocytes, as well as extramedullary myelopoiesis. Peritoneal macrophages from ACE-KO mice were deficient in the production of effector molecules, such as tumor necrosis factor-α, interleukin-12p40, and CD86 when stimulated with lipopolysaccharide and interferon-γ. ACE-KO mice were more susceptible to Staphylococcus aureus infection. Further studies using total or fractionated bone marrows revealed that ACE regulates myeloid proliferation, differentiation, and functional maturation via angiotensin II and substance P and through the angiotensin II receptor type 1 and substance P neurokinin 1 receptors. Angiotensin II was correlated with CCAAT-enhancer-binding protein-α up-regulation during myelopoiesis. Angiotensin II supplementation of ACE-KO mice rescued macrophage functional maturation. These results demonstrate a previous unrecognized significant role for ACE in myelopoiesis and imply new perspectives for manipulating myeloid cell expansion and maturation.
authors.affiliation: Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Chentao
authors.initials: C
authors.lastname: Lin
authors.forename: Vivekanand
authors.initials: V
authors.lastname: Datta
authors.forename: Derick
authors.initials: D
authors.lastname: Okwan-Duodu
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fuchs
authors.forename: Randa
authors.initials: R
authors.lastname: Alsabeh
authors.forename: Sandrine
authors.initials: S
authors.lastname: Billet
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Xiao Z
authors.initials: XZ
authors.lastname: Shen
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D017706:Lisinopril / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D013373:Substance P / Q000502:physiology; D015854:Up-Regulation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D022763:CCAAT-Enhancer-Binding Protein-alpha; D000804:Angiotensin II; D013373:Substance P; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A