Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia

• Published in: PloS one 2014-01, Vol.9 (1), p.e86135
• Main Authors: Wijnands, Karolina A P, Hoeksema, Marten A, Meesters, Dennis M, van den Akker, Nynke M S, Molin, Daniel G M, Briedé, Jacob J, Ghosh, Mitrajit, Köhler, S Eleonore, van Zandvoort, Marc A M J, de Winther, Menno P J, Buurman, Wim A, Lamers, Wouter H, Poeze, Martijn
• Format: Article
• Language: English
• Subjects: Anatomy & physiology; Animals; Arginase; Arginase - metabolism; Arginine; Arginine - blood; Bioavailability; Biochemistry; Biology; Bone marrow; Cell Count; Citrulline - blood; Cloning; Comparative analysis; Cytokines - biosynthesis; Embryology; Endothelial cells; Endothelium; Endotoxemia; Endotoxemia - blood; Endotoxemia - enzymology; Endotoxins; Enzymes; Immune response; Inflammation; Inflammatory response; Integrases - metabolism; Jejunum - blood supply; Jejunum - enzymology; Jejunum - pathology; Lipopolysaccharides; Macrophages; Macrophages - metabolism; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microcirculation; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Nitrites - metabolism; Nutrition; Organ Specificity - drug effects; Ornithine - blood; Perfusion; Peroxidase - metabolism; Physicians; Physiology; Polyamines; Receptor, TIE-2 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sepsis; Substrates; Surgery; Toxicology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086135

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 Arg1(fl/fl)/Tie2-Cre(tg/-) 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. 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 Arg1(fl/fl)/Tie2-Cre(tg/-) mice following infusion of the NOS2 inhibitor 1400W further implicated NOS2 in the enhanced capacity to produce NO production Arg1(fl/fl)/Tie2-Cre(tg/-) mice. Reduced arginase-1 activity in Arg1(fl/fl)/Tie2-Cre(tg/-) 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.