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

Abstract

Rationale and objectiveArginase-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 ResultsArginase-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.ConclusionsReduced 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.

Deletion of endothelial arginase 1 does not improve vasomotor function in diabetic mice

“…In fact, in a previous study with these mice, we observed effects of Arg1 ablation that could be attributed to either macrophages (cytokine production) or endothelium (NOS‐dependent effects on the mucosal perfusion of villi in the jejunum) (Wijnands et al. ). However, it is highly unlikely that substantial numbers of erythrocytes and macrophages were present in the walls of the vessels used in the wire‐myograph measurements.…”

“…Furthermore, we showed earlier that lipopolysaccharide‐treated Arg1‐KO Tie2 mice produced more NO in the endothelium of their carotid arteries and jejunum than control mice (Wijnands et al. ). In addition, Arg1‐KO Tie2 mice suffering from allergic asthma did not express ARG1 mRNA or protein in their lungs, even though this condition upregulates Arg1 expression >200‐fold in control mice (Cloots et al.…”

“…In the jejunum of untreated Arg1‐KO Tie2 mice, on the other hand, NOS3 was hypo‐phosphorylated on Thr495 and tended to be hyper‐phosphorylated on Ser1177 (Wijnands et al. ), suggesting that Arg1 deficiency indeed increased NOS3 activity (Chen et al. ; Lin et al.…”

Nuclear Receptor Nr4a2 Promotes Alternative Polarization of Macrophages and Confers Protection in Sepsis

“…Ornithine is a precursor for polyamines and intermediates that give rise to collagen for wound healing and tissue repair (46). Moreover, BMDMs obtained from mice lacking arginase 1 are more susceptible to LPS-induced endotoxin as they show increased production of pro-inflammatory mediators as compared with BMDMs from wild-type mice (47). Various transcription factors have been shown to regulate arginase 1 expression in response to various stimuli.…”

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

“…As arginine is a substrate for both endothelial and inducible nitric oxide synthase (eNOS, iNOS), nitric oxide (NO) synthesis rises with increasing arginine supply (Nagasaka et al 2009;Loscalzo 2003;Wijnands et al 2014). NO is a vasoprotective agent, regulating blood vessel diameter and compliance (Schulze et al 2004;Schulze et al 2006).…”