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ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

ABSTRACT: Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5? (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.

SUBMITTER: Cao DY

PROVIDER: S-EPMC6996878 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

Cao Duo-Yao DY Spivia Weston R WR Veiras Luciana C LC Khan Zakir Z Peng Zhenzi Z Jones Anthony E AE Bernstein Ellen A EA Saito Suguru S Okwan-Duodu Derick D Parker Sarah J SJ Giani Jorge F JF Divakaruni Ajit S AS Van Eyk Jennifer E JE Bernstein Kenneth E KE

The Journal of biological chemistry 20191223 5

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by ...[more]

PMID: 31871049

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Project description:PurposeRadiation-induced lung injury is a major dose-limiting toxicity for thoracic radiation therapy patients. In experimental models, treatment with angiotensin converting enzyme (ACE) inhibitors mitigates radiation pneumonitis; however, the mechanism of action is not well understood. Here, we evaluate the direct role of ACE inhibition on lung immune cells.Methods and materialsACE expression and activity were determined in the lung immune cell compartment of irradiated adult rats after either high dose fractionated radiation therapy to the right lung (5 fractions × 9 Gy) or a single dose of 13.5 Gy partial body irradiation. Mitigation of radiation-induced pneumonitis with the ACE-inhibitor lisinopril was evaluated in the 13.5 Gy rat partial body irradiation model. During pneumonitis, we characterized inflammation and immune cell content in the lungs and bronchoalveolar lavage fluid. In vitro mechanistic studies were performed using primary human monocytes and the human monocytic THP-1 cell line.ResultsIn both the partial body irradiation and fractionated radiation therapy models, radiation increased ACE activity in lung immune cells. Treatment with lisinopril improved survival during radiation pneumonitis (P = .0004). Lisinopril abrogated radiation-induced increases in bronchoalveolar lavage fluid monocyte chemoattractant protein 1 (chemokine ligand 2) and MIP-1a cytokine levels (P < .0001). Treatment with lisinopril reduced both ACE expression (P = .006) and frequency of CD45+ CD11b+ lung myeloid cells (P = .004). In vitro, radiation injury acutely increased ACE activity (P = .045) and reactive oxygen species (ROS) generation (P = .004) in human monocytes, whereas treatment with lisinopril blocked radiation-induced increases in both ACE and ROS. Radiation-induced ROS generation was blocked by pharmacologic inhibition of either NADPH oxidase 2 (P = .012) or the type 1 angiotensin receptor (P = .013).ConclusionsThese data demonstrate radiation-induced ACE activation within the immune compartment promotes the pathogenesis of radiation pneumonitis, while ACE inhibition suppresses activation of proinflammatory immune cell subsets. Mechanistically, our in vitro data demonstrate radiation directly activates the ACE/type 1 angiotensin receptor pathway in immune cells and promotes generation of ROS via NADPH oxidase 2.

Project description:Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

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ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

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ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

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