Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California, USA.
FASEB J. 2011 Apr;25(4):1145-55. doi: 10.1096/fj.10-169433. Epub 2010 Dec 9.
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.
血管紧张素转换酶（ACE）的抑制会在人类和小鼠中引起贫血，但尚不清楚 ACE 是否参与造血的其他方面。在这里，我们系统地评估了 ACE 敲除（KO）小鼠，发现其具有骨髓髓系前体细胞和髓系细胞增多为特征的髓系异常，以及骨髓外髓系生成。当用脂多糖和干扰素-γ刺激时，来自 ACE-KO 小鼠的腹膜巨噬细胞在产生效应分子（如肿瘤坏死因子-α、白细胞介素-12p40 和 CD86）方面存在缺陷。ACE-KO 小鼠更容易受到金黄色葡萄球菌感染。使用全骨髓或骨髓分馏进行的进一步研究表明，ACE 通过血管紧张素 II 和 P 物质以及血管紧张素 II 受体 1 和 P 物质神经激肽 1 受体调节髓系增殖、分化和功能成熟。血管紧张素 II 与髓系生成过程中 CCAAT 增强子结合蛋白-α的上调相关。向 ACE-KO 小鼠中补充血管紧张素 II 可挽救巨噬细胞功能成熟。这些结果表明 ACE 在髓系生成中具有以前未被认识的重要作用，并暗示了操纵髓系细胞扩增和成熟的新视角。
