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


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 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.


CONCLUSIONS
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.
Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands ; NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Karolina A P
KA
Wijnands
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Marten A
MA
Hoeksema
Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands ; NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Dennis M
DM
Meesters
Department of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands ; CARIM Cardiovascular Research Institute of Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Physiology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Nynke M S
NM
van den Akker
CARIM Cardiovascular Research Institute of Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Physiology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Daniel G M
DG
Molin
Department of Toxicogenomics, Maastricht University Medical Centre, Maastricht, the Netherlands ; GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Jacob J
JJ
Briedé
CARIM Cardiovascular Research Institute of Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Genetics & cell Biology, Section Molecular Cell Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Mitrajit
M
Ghosh
NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Anatomy & Embryology, Maastricht University Medical Centre, Maastricht, the Netherlands.
S Eleonore
SE
Köhler
CARIM Cardiovascular Research Institute of Maastricht, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Genetics & cell Biology, Section Molecular Cell Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Marc A M J
MA
van Zandvoort
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Menno P J
MP
de Winther
Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands ; NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Wim A
WA
Buurman
NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands ; Department of Anatomy & Embryology, Maastricht University Medical Centre, Maastricht, the Netherlands.
Wouter H
WH
Lamers
Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands ; NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
Martijn
M
Poeze
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000097:blood*; D002452:Cell Count; D002956:Citrulline / Q000097:blood; D016207:Cytokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000097:blood* / Q000201:enzymology*; D019426:Integrases / Q000378:metabolism; D007583:Jejunum / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D009952:Ornithine / Q000097:blood; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D009573:Nitrites; D012333:RNA, Messenger; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D009952:Ornithine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C045073:Cre recombinase; D019426:Integrases; C544448:Arg1 protein, mouse; D001119:Arginase