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Requirement of argininosuccinate lyase for systemic nitric oxide production.

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

Pubmed ID: 22081021

Authors

  • Erez A
  • Nagamani SC
  • Shchelochkov OA
  • Premkumar MH
  • Campeau PM
  • Chen Y
  • Garg HK
  • Li L
  • Mian A
  • Bertin TK
  • Black JO
  • Zeng H
  • Tang Y
  • Reddy AK
  • Summar M
  • O'Brien WE
  • Harrison DG
  • Mitch WE
  • Marini JC
  • Aschner JL
  • Bryan NS
  • Lee B

Journal

Nature medicine

Publication Data

December 7, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK081735
  • Agency: NIDDK NIH HHS, Id: DK37175
  • Agency: NIDDK NIH HHS, Id: DK54450
  • Agency: NIGMS NIH HHS, Id: GM07526
  • Agency: NIGMS NIH HHS, Id: GM90310
  • Agency: NHLBI NIH HHS, Id: HL75511
  • Agency: NIGMS NIH HHS, Id: R01 GM090310
  • Agency: NHLBI NIH HHS, Id: R01 HL022512
  • Agency: NHLBI NIH HHS, Id: R01 HL022512-34
  • Agency: NIDDK NIH HHS, Id: R37 DK037175
  • Agency: NCRR NIH HHS, Id: RR00188
  • Agency: NCRR NIH HHS, Id: RR024173
  • Agency: NCRR NIH HHS, Id: RR19453
  • Agency: Canadian Institutes of Health Research, Id:

Mesh Terms

  • Animals
  • Arginine
  • Argininosuccinate Lyase
  • Argininosuccinate Synthase
  • Argininosuccinic Aciduria
  • Cell Line
  • Disease Models, Animal
  • Endothelial Cells
  • Female
  • Fibroblasts
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitrites
  • RNA, Small Interfering
  • Sequence Analysis, DNA
  • Swine