Angiotensin‐converting enzyme is required for normal myelopoiesis

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.—Lin, C., Datta, V., Okwan‐Duodu, D., Chen, X., Fuchs, S., Alsabeh, R., Billet, S., Bernstein, K. E., Shen, X. Z. Angiotensin‐converting enzyme is required for normal myelopoiesis. FASEB J. 25, 1145–1155 (2011). www.fasebj.org