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Angiotensin‐converting enzyme (ACE) up‐regulates metabolic function in myeloid‐derived cells
Author(s) -
Cao DuoYao,
Khan Zakir,
Peng ZhenZi,
Giani Jorge F,
Veiras Luciana C,
Chang Corey,
Bernstein Ellen,
Bernstein Kenneth
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.794.1
Subject(s) - percoll , immune system , chemistry , angiotensin converting enzyme , innate immune system , enzyme , myeloid , macrophage , medicine , endocrinology , biochemistry , biology , immunology , in vitro , blood pressure
While most studies of ACE focus on the blood pressure effects of angiotensin II, it is now recognized that ACE also plays an important role in both the innate and adaptive immune responses1. To study the mechanism of this effect, we made two mouse strains: ACE 10/10, which over‐express ACE in macrophages, and NeuACE, which over‐express ACE in neutrophils. NeuACE and ACE 10/10 mice have a better immune response in several different disease models (e.g. bacteria, tumor, Alzheimer's disease)1,2. We hypothesized that ACE affects myeloid function by inducing changes in cellular energy metabolism. To examine this, metabolic intermediates were studied by mass spectrometry and chemical methods in ACE over‐expressing cells. Methods Neutrophils were isolated from bone marrow; macrophages were collected from the peritoneum 4 days after thioglycolate injection. Cells were purified by Percoll gradient. Results Mass spec. showed more than 32 differences, with virtually all affected metabolites increased in the ACE over expressing cells. In ACE 10/10 macrophages, cellular ATP, ADP and AMP was 3.4‐, 2.7‐, and 2.7‐fold the levels in WT cells. In NeuACE neutrophils, the pattern was the same but numerically less than in macrophages. Chemical analysis showed a 2.8‐fold and a 1.5‐fold increase of cellular ATP in ACE 10/10 macrophages and NeuACE neutrophils. In ACE 10/10 macrophages, the ATP/ADP ratio was 2.1 vs. 1.4 for WT cells. For NeuACE neutrophils, the ATP/ADP ratio was 3.0 vs. 1.9 in WT neutrophils. The increase of cellular ATP is due to the catalytic activity of ACE; when animals were treated with an ACE inhibitor, peritoneal macrophages or bone marrow derived neutrophils showed ATP levels that were no different from similarly treated WT mice. The effect of ACE is not due to increased angiotensin II. Conclusions ACE overexpression in macrophages or neutrophils of mice upregulates ATP concentrations in these immune cells. This is due to the catalytic activity of ACE but not the production of angiotensin II. Increased cellular ATP plays an important role in the enhanced innate and adaptive immune ability of myeloid cells over expressing ACE. Support or Funding Information NIH P01 HL129941 and R01 AI143599This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .