Requirement of argininosuccinate lyase for systemic nitric oxide production

Ayelet Erez, Sandesh C S Nagamani, Oleg A. Shchelochkov, Muralidhar H. Premkumar, Philippe M. Campeau, Yuqing Chen, Harsha K. Garg, Li Li, Asad Mian, Terry K. Bertin, Jennifer O. Black, Heng Zeng, Yaoping Tang, Anilkumar K. Reddy, Marshall Summar, William E. O'Brien, David G. Harrison, William E. Mitch, Juan C. Marini, Judy L. Aschner & 2 others Nathan S. Bryan, Brendan Lee

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1619-1626
Number of pages8
JournalNature Medicine
Volume17
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

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Argininosuccinate Lyase
Nitric Oxide
Nitric Oxide Synthase
Arginine
Argininosuccinic Aciduria
Physiological Phenomena
Multiprotein Complexes
Nitric Oxide Donors
Pathologic Processes
Nitrites
Blood Vessels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Erez, A., Nagamani, S. C. S., Shchelochkov, O. A., Premkumar, M. H., Campeau, P. M., Chen, Y., ... Lee, B. (2011). Requirement of argininosuccinate lyase for systemic nitric oxide production. Nature Medicine, 17(12), 1619-1626. https://doi.org/10.1038/nm.2544

Requirement of argininosuccinate lyase for systemic nitric oxide production. / Erez, Ayelet; Nagamani, Sandesh C S; Shchelochkov, Oleg A.; Premkumar, Muralidhar H.; Campeau, Philippe M.; Chen, Yuqing; Garg, Harsha K.; Li, Li; Mian, Asad; Bertin, Terry K.; Black, Jennifer O.; Zeng, Heng; Tang, Yaoping; Reddy, Anilkumar K.; Summar, Marshall; O'Brien, William E.; Harrison, David G.; Mitch, William E.; Marini, Juan C.; Aschner, Judy L.; Bryan, Nathan S.; Lee, Brendan.

In: Nature Medicine, Vol. 17, No. 12, 12.2011, p. 1619-1626.

Research output: Contribution to journalArticle

Erez, A, Nagamani, SCS, 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 2011, 'Requirement of argininosuccinate lyase for systemic nitric oxide production', Nature Medicine, vol. 17, no. 12, pp. 1619-1626. https://doi.org/10.1038/nm.2544
Erez A, Nagamani SCS, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nature Medicine. 2011 Dec;17(12):1619-1626. https://doi.org/10.1038/nm.2544
Erez, Ayelet ; Nagamani, Sandesh C S ; Shchelochkov, Oleg A. ; Premkumar, Muralidhar H. ; Campeau, Philippe M. ; Chen, Yuqing ; Garg, Harsha K. ; Li, Li ; Mian, Asad ; Bertin, Terry K. ; Black, Jennifer O. ; Zeng, Heng ; Tang, Yaoping ; Reddy, Anilkumar K. ; Summar, Marshall ; O'Brien, William E. ; Harrison, David G. ; Mitch, William E. ; Marini, Juan C. ; Aschner, Judy L. ; Bryan, Nathan S. ; Lee, Brendan. / Requirement of argininosuccinate lyase for systemic nitric oxide production. In: Nature Medicine. 2011 ; Vol. 17, No. 12. pp. 1619-1626.
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