l-Citrulline recycling by argininosuccinate synthetase and lyase in rat gastric fundus

Geldre, Lieve A Van; Timmermans, Jean‐Pierre; Lefebvre, Romain

doi:10.1016/s0014-2999(02)02584-0

Cited by 13 publications

(7 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In neurons, colocalization of neuronal NOS, AS, and AL was identified in the canine gastrointestinal tract providing morphological evidence of a citrulline-NO cycle (43). Finally, in the rat gastric fundus, functional evidence of recycling is supported by colocalization of AS, AL, and nNOS (44).…”

Section: Table Imentioning

confidence: 83%

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Goodwin

Solomonson

Eichler

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Although cellular levels of arginine greatly exceed the apparent K m for endothelial nitric-oxide synthase, current evidence suggests that the bulk of this arginine may not be available for nitric oxide (NO) production. We propose that arginine regeneration, that is the recycling of citrulline back to arginine, defines the essential source of arginine for NO production. To support this proposal, RNA interference analysis was used to selectively reduce the expression of argininosuccinate synthase (AS), because the only known metabolic role for AS in endothelial cells is in the regeneration of L-arginine from L-citrulline. Western blot analysis demonstrated a significant and dose-dependent reduction of AS protein as a result of AS small interfering RNA treatment with a corresponding diminished capacity to produce basal or stimulated levels of NO, despite saturating levels of arginine in the medium. Unanticipated, however, was the finding that the viability of AS small interfering RNA-treated endothelial cells was significantly decreased when compared with control cells. Trypan blue exclusion analysis suggested that the loss of viability was not because of necrosis. Two indicators, reduced expression of Bcl-2 and an increase in caspase activity, which correlated directly with reduced expression of AS, suggested that the loss of viability was because of apoptosis. The exposure of cells to an NO donor prevented apoptosis associated with reduced AS expression. Overall, these results demonstrate the essential role of AS for endothelial NO production and cell viability.Nitric oxide (NO) 1 is an important modulator for a wide range of functions including vasodilation of blood vessels, immune system function, angiogenesis, inhibition of leukocyte adhesion and platelet aggregation, gene regulation, and apoptosis (1-3). Moreover, NO has a dual role in cell viability depending on the tissue type and concentration. Either very high or very low concentrations of NO may induce cell death, whereas basal concentrations may inhibit apoptosis (4 -7). Previous work has shown that NO protects against serum starvation-(8), H 2 O 2 -(9), TNF-␣-(10), and oxidized low density lipoprotein-induced apoptosis (11, 12) in endothelial cells.Argininosuccinate synthase (AS), the rate-limiting step (13) in the regeneration of arginine from citrulline, catalyzes the synthesis of argininosuccinate, AMP, and inorganic pyrophosphate from citrulline, ATP, and aspartate. Argininosuccinate is then cleaved by argininosuccinate lyase (AL) to produce Larginine and fumarate. In the liver, AS and AL function together as components of the urea cycle, ultimately to form arginine from citrulline. Although the expression of AS and AL in the liver is high, both enzymes are found in most mammalian tissues, although at significantly lower levels. The discovery of arginine-derived NO, catalyzed by nitric-oxide synthases (NOSs), revealed a second role for AS and AL (1-3). Together with NOS, they function as part of a citrulline-NO cycle where AS and AL convert citrul...

show abstract

Section: Table Imentioning

confidence: 83%

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Goodwin

Solomonson

Eichler

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To complete the urea cycle, L-ornithine is produced from L-arginine by the enzyme arginase and then transformed to L-citrulline via ornithine transcarbamoylase [9]. In rat gastric fundus, co-localization of nNOS with AS and AL has been shown in the nerve fibres of the longitudinal smooth muscle, suggesting that L-citrulline could be converted to L-arginine to supply substrate to nNOS [26]. The recycling of L-citrulline to L-arginine may also be important to maintain the EFS-elicited relaxations in pig urethra.…”

Section: Discussionmentioning

confidence: 99%

The effects of exogenous amino acids on the relaxant responses of pig urethral smooth muscle evoked by stimulation of the inhibitory nitrergic nerves

Durlu

Brading

2004

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

Inhibitory innervation of urethral smooth muscle is mediated partly through release of NO. We investigated the mechanisms involved in the supply of the substrate L: -arginine to NO synthase by examining the relaxant response of the muscle to electrical field stimulation (EFS) and the effects of addition of amino acids to the bathing medium. Relaxant responses persisted during hours of repetitive stimulation but were enhanced rapidly by addition of L: -arginine (the "arginine paradox"). Addition of L: -lysine (competes with L: -arginine for transport on the y(+) carrier) and L: -glutamine (competing on the y(+)L carrier) attenuated the enhancement. Enhancement persisted after washing but was reversed by application of L: -lysine, suggesting that exogenous L: -arginine fills an intracellular pool and that L: -lysine can trans-stimulate its efflux from the pool. After prolonged depolarization in high-K(+), Na(+)-free solution the relaxant response became purely nitrergic. Addition of L: -arginine during the exposure continued to enhance the subsequent responses but L: -glutamine added with L: -arginine, could no longer reduce this enhancement. The results show the arginine paradox in inhibitory nerves and suggest the involvement of y(+) and y(+)L carriers in the transport of L: -arginine.

show abstract

“…The L-arginine availability may also be regulated by recycling of the NOS-product L-citrulline, through the L-citrulline/L-arginine cycle [22,23]. This cycle consists of the enzymes L-argininosuccinate synthase and Largininosuccinate-lyase (ASS and ASL, respectively), which, in various tissues, are colocalized and coinduced with NOS isozymes [23][24][25][26][27]. Although recycling of L-citrulline does not play a role in iNANC NO-mediated relaxations of human and guinea pig airway smooth muscle under basal conditions, the inhibitory effect of the NOS-inhibitor Nnitro-L-arginine was reversed by L-citrulline [28,29], which was prevented by ASS and ASL inhibitors, indicating that the L-citrulline/L-arginine cycle is effective under conditions of low L-arginine utilization by NOS1 [29].…”

Section: Nitric Oxide Homeostasis and Airway Functionmentioning

confidence: 99%

Arginase in Asthma Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!

North¹,

Zaagsma²,

Scott³

et al. 2010

TONOJ

View full text Add to dashboard Cite

Abstract:The enzyme, arginase, converts L-arginine into L-ornithine and urea, and has been implicated in the pathogenesis of lung diseases, related to dysregulation of L-arginine metabolism and remodeling. Allergic asthma is a chronic condition characterized by inflammation, lung remodeling and airways hyperresponsiveness (AHR). Increased expression of arginase may contribute to AHR in asthma by reducing L-arginine bioavailability for the nitric oxide synthase (NOS) isozymes, thus, limiting the production of the endogenous bronchodilator, nitric oxide (NO). Reduction of intracellular L-arginine concentrations as a consequence of augmented arginase expression and activity may also promote NOS uncoupling, resulting in increased formation of peroxynitrite, a powerful oxidant that promotes bronchoconstriction and inflammation. In chronic asthma, increased arginase expression may also contribute to airways remodeling, through increased synthesis of L-ornithine, and hence the production of polyamines and L-proline, which are involved in cell proliferation and collagen deposition, respectively. New drugs targeting the arginase pathway could have therapeutic benefits in asthma. This review focuses on recent developments in our understanding of the role of arginase in AHR, inflammation and remodeling, highlighting studies that advance our knowledge of L-arginine dysregulation in human asthma and animal studies that explore the therapeutic potential of arginase inhibition.

show abstract

l-Citrulline recycling by argininosuccinate synthetase and lyase in rat gastric fundus

Cited by 13 publications

References 27 publications

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

The effects of exogenous amino acids on the relaxant responses of pig urethral smooth muscle evoked by stimulation of the inhibitory nitrergic nerves

Arginase in Asthma Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!

Contact Info

Product

Resources

About

l-Citrulline recycling by argininosuccinate synthetase and lyase in rat gastric fundus

Cited by 13 publications

References 27 publications

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

Argininosuccinate Synthase Expression Is Required to Maintain Nitric Oxide Production and Cell Viability in Aortic Endothelial Cells

The effects of exogenous amino acids on the relaxant responses of pig urethral smooth muscle evoked by stimulation of the inhibitory nitrergic nerves

Arginase in Asthma  Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!

Contact Info

Product

Resources

About

Arginase in Asthma Recent Developments in Animal and Human Studies~!2009-11-12~!2010-03-23~!2010-05-04~!