Arginase-1 Deficiency Regulates Arginine Concentrations and NOS2-Mediated NO Production during Endotoxemia

Rationale and objective Arginase-1 is an important component of the intricate mechanism regulating arginine availability during immune responses and nitric oxide synthase (NOS) activity. In this study Arg1fl/fl/Tie2-Cretg/− mice were developed to investigate the effect of arginase-1 related arginine depletion on NOS2- and NOS3-dependent NO production and jejunal microcirculation under resting and endotoxemic conditions, in mice lacking arginase-1 in endothelial and hematopoietic cells. Methods and Results Arginase-1-deficient mice as compared with control mice exhibited higher plasma arginine concentration concomitant with enhanced NO production in endothelial cells and jejunal tissue during endotoxemia. In parallel, impaired jejunal microcirculation was observed in endotoxemic conditions. Cultured bone-marrow-derived macrophages of arginase-1 deficient animals also presented a higher inflammatory response to endotoxin than control littermates. Since NOS2 competes with arginase for their common substrate arginine during endotoxemia, Nos2 deficient mice were also studied under endotoxemic conditions. As Nos2−/− macrophages showed an impaired inflammatory response to endotoxin compared to wild-type macrophages, NOS2 is potentially involved. A strongly reduced NO production in Arg1fl/fl/Tie2-Cretg/− mice following infusion of the NOS2 inhibitor 1400W further implicated NOS2 in the enhanced capacity to produce NO production Arg1fl/fl/Tie2-Cretg/− mice. Conclusions Reduced arginase-1 activity in Arg1fl/fl/Tie2-Cretg/− mice resulted in increased inflammatory response and NO production by NOS2, accompanied by a depressed microcirculatory flow during endotoxemia. Thus, arginase-1 deficiency facilitates a NOS2-mediated pro-inflammatory activity at the expense of NOS3-mediated endothelial relaxation.

• Publication year

  2014

• Venue

  PLoS ONE

• Publication date

  2014-01-21

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1371/journal.pone.0086135PMID 24465919PMCID 3897658
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice.

  2013cited by this paper
• Specific Visualization of Nitric Oxide in the Vasculature with Two-Photon Microscopy Using a Copper Based Fluorescent Probe

  2013cited by this paper
• Molecular Pathways Regulating Macrophage Polarization: Implications for Atherosclerosis

  2012cited by this paper
• Citrulline a More Suitable Substrate than Arginine to Restore NO Production and the Microcirculation during Endotoxemia

  2012cited by this paper
• Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities.

  2012cited by this paper
• Role of reactive oxygen and nitrogen species in the vascular responses to inflammation.

  2012cited by this paper
• Pivotal Advance: Arginase‐1‐independent polyamine production stimulates the expression of IL‐4‐induced alternatively activated macrophage markers while inhibiting LPS‐induced expression of inflammatory genes

  2012cited by this paper
• Regulation of nitric oxide production in health and disease

  2010cited by this paper
• Arginase: an emerging key player in the mammalian immune system

  2009cited by this paper
• Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production.

  2009cited by this paper
• Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.

  2009cited by this paper
• Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis

  2009cited by this paper
• Recent advances in arginine metabolism: roles and regulation of the arginases.

  2009cited by this paper
• Microcirculation and mitochondria in sepsis: getting out of breath

  2009cited by this paper
• Arginine and arginase: endothelial NO synthase double crossed?

  2008cited by this paper
• Endothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis

  2008cited by this paper
• Exogenous arginine in sepsis

  2007cited by this paper
• ARGINASE: A CRITICAL REGULATOR OF NITRIC OXIDE SYNTHESIS AND VASCULAR FUNCTION

  2007cited by this paper
• Polyamine homeostasis in arginase knockout mice.

  2007cited by this paper
• Systemic NO production during (septic) shock depends on parenchymal and not on hematopoietic cells: in vivo iNOS expression pattern in (septic) shock

  2006cited by this paper
• Knockdown of Arginase I Restores NO Signaling in the Vasculature of Old Rats

  2006cited by this paper
• Ornithine deficiency in the arginase double knockout mouse.

  2006cited by this paper
• Constitutive eNOS-derived nitric oxide is a determinant of endothelial junctional integrity.

  2005cited by this paper
• The role of arginine in infection and sepsis.

  2005cited by this paper
• Arginine metabolism in vascular biology and disease

  2005cited by this paper
• Arginine metabolism in vascular biology and disease

  2005cited by this paper
• The microcirculation is the motor of sepsis

  2005cited by this paper
• Arginases I and II: do their functions overlap?

  2004cited by this paper
• Sepsis: An arginine deficiency state?

  2004cited by this paper
• Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells.

  2004cited by this paper
• Arginase pathway in human endothelial cells in pathophysiological conditions.

  2004cited by this paper
• Ischemia‐reperfusion selectively impairs nitric oxide‐ mediated dilation in coronary arterioles: counteracting role of arginase

  2003cited by this paper
• Arginine availability, arginase, and the immune response

  2003cited by this paper
• Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels

  2003influential reference
• Myeloperoxidase up-regulates the catalytic activity of inducible nitric oxide synthase by preventing nitric oxide feedback inhibition

  2003cited by this paper
• Quantitative in vivo assessment of arginine utilization and nitric oxide production in endotoxemia.

  2002cited by this paper
• Mouse Model for Human Arginase Deficiency

  2002cited by this paper
• Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide‐mediated vasodilatory function

  2001cited by this paper
• Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells.

  2001cited by this paper
• Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase.

  2001cited by this paper
• Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo.

  2001cited by this paper
• Arginase I Expression and Activity in Human Mononuclear Cells After Injury

  2001cited by this paper
• Trauma increases extrahepatic arginase activity.

  2000cited by this paper
• Arginase I: a limiting factor for nitric oxide and polyamine synthesis by activated macrophages?

  2000cited by this paper
• Arginase modulates nitric oxide production in activated macrophages.

  1998cited by this paper
• A modular set of Flp, FRT and lacZ fusion vectors for manipulating genes by site-specific recombination.

  1996cited by this paper
• Downregulation of endothelial constitutive nitric oxide synthase expression by lipopolysaccharide.

  1996cited by this paper
• Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysaccharide treatment in vivo in the rat.

  1996cited by this paper
• l‐Arginine depletion by arginase reduces nitric oxide production in endotoxic shock: an electron paramagnetic resonance study

  1995cited by this paper
• Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death.

  1995cited by this paper
• New insights into the regulation of inducible nitric oxide synthesis.

  1994cited by this paper
• Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta

  1993cited by this paper
• Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets.

  1993cited by this paper
• Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.

  1993cited by this paper
• Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide.

  1993cited by this paper
• Cloning and characterization of inducible nitric oxide synthase from mouse macrophages.

  1992cited by this paper
• Nitrogen oxide levels in patients after trauma and during sepsis.

  1991cited by this paper
• Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1.

  1988cited by this paper
• Site-specific recombination

  1981cited by this paper

• Arginine metabolism in myeloid cells in health and disease

  2025cites this paper
• Biochemistry, pharmacology, and in vivo function of arginases

  2024cites this paper
• Untargeted metabolic profiling of high-dose methotrexate toxicity shows alteration in betaine metabolism

  2024cites this paper
• Endothelial cell metabolism in sepsis.

  2023cites this paper
• Fructose: a modulator of intestinal barrier function and hepatic health?

  2023cites this paper
• Multi-Omics Endotypes in ICU Sepsis-Induced Immunosuppression

  2023cites this paper
• H1N1 Influenza Virus-Infected Nasal Mucosal Epithelial Progenitor Cells Promote Dendritic Cell Recruitment and Maturation

  2022cites this paper
• Arginine Availability in Reamed Intramedullary Aspirate as Predictor of Outcome in Nonunion Healing

  2022cites this paper
• Downregulation of eNOS and preserved endothelial function in endothelial-specific arginase 1-deficient mice.

  2022cites this paper
• Alterations of nitric oxide homeostasis as trigger of intestinal barrier dysfunction in non‐alcoholic fatty liver disease

  2022cites this paper
• Activated M1 macrophages suppress c-kit expression via TNF-α-mediated upregulation of miR-222 in Neonatal Necrotizing Enterocolitis

  2021cites this paper
• Microcirculatory Function during Endotoxemia—A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation

  2021cites this paper
• Regulation of T Cells in Cancer by Nitric Oxide

  2021cites this paper
• Pathological Features of Enterovirus 71-Associated Brain and Lung Damage in Mice Based on Quantitative Proteomic Analysis

  2021cites this paper
• Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase

  2021cites this paper
• The acidified drinking water-induced changes in the behavior and gut microbiota of wild-type mice depend on the acidification mode

  2021cites this paper
• Derangement of Arginine and Related Amino Acids in Children Undergoing Surgery for Congenital Heart Disease With Cardiopulmonary Bypass

  2020cites this paper
• TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation

  2020cites this paper
• Arginine and Endothelial Function

  2020cites this paper
• A randomized-controlled trial of arginine infusion in severe sepsis on microcirculation and metabolism.

  2020cites this paper
• Immunometabolism and Sepsis: A Role for HIF?

  2019cites this paper
• Bench to bedside review: therapeutic modulation of nitric oxide in sepsis—an update

  2019cites this paper
• Identification of agmatinase from Vibrio splendidus and its roles in modulating arginine metabolism of Apostichopus japonicus

  2018cites this paper
• ALTERNATIVELY ACTIVATED MACROPHAGES IN PSEUDOMONAS AERUGINOSA PNEUMONIA: MODULATION OF THE NF-ΚB SIGNALING PATHWAY AND THE IMMUNOMODULATORY ROLE OF ARGINASE-1

  2018influential citation
• Protein translation associated to PERK arm is a new target for regulation of metainflammation: A connection with hepatocyte cholesterol

  2018cites this paper
• Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice

  2018cites this paper
• Arginase-1 Expression in Myeloid Cells Regulates Staphylococcus aureus Planktonic but Not Biofilm Infection

  2018cites this paper
• Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis.

  2017cites this paper
• Nitric oxide production by peritoneal macrophages from aged rats: A short term and direct modulation by citrulline.

  2017cites this paper
• Bone marrow transplantation in mice as a tool to study M2 macrophage activation in atherogenesis

  2017cites this paper
• Cellular metabolism of myeloid cells in sepsis

  2017cites this paper
• Extracellular superoxide dismutase is necessary to maintain renal blood flow during sepsis development

  2017cites this paper
• Cloning and comparative analysis the proximal promoter activities of arginase and agmatinase genes in Apostichopus japonicus.

  2016cites this paper
• CRISPR/Cas9-Mediated Gene Editing of ARG1 in Cell Lines and Primary Cells

  2016cites this paper
• Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

  2016cites this paper
• The first description of complete invertebrate arginine metabolism pathways implies dose-dependent pathogen regulation in Apostichopus japonicus

  2016cites this paper
• Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis*♦

  2015cites this paper
• Implicación de la actividad Arginasa en la respuesta inflamatoria sistémica inducida en los pacientes sometidos a Cirugía Cardiaca con Bypass Cardiopulmonar

  2015cites this paper
• Arginine and Citrulline and the Immune Response in Sepsis

  2015influential citation
• Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study.

  2015cites this paper
• Longitudinal quantification of radical bursts during pulmonary ischaemia and reperfusion.

  2015cites this paper
• Arginase-1 deficiency

  2015cites this paper
• Expression of arginase I and inducible nitric oxide synthase in the peripheral blood and lymph nodes of HIV-positive patients

  2015cites this paper