@article{8245137bfe544af9a7472da088fab9c1,
title = "Requirement of argininosuccinate lyase for systemic nitric oxide production",
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.",
author = "Ayelet Erez and Nagamani, {Sandesh C.S.} and Shchelochkov, {Oleg A.} and Premkumar, {Muralidhar H.} and Campeau, {Philippe M.} and Yuqing Chen and Garg, {Harsha K.} and Li Li and Asad Mian and Bertin, {Terry K.} and Black, {Jennifer O.} and Heng Zeng and Yaoping Tang and Reddy, {Anilkumar K.} and Marshall Summar and O'Brien, {William E.} and Harrison, {David G.} and Mitch, {William E.} and Marini, {Juan C.} and Aschner, {Judy L.} and Bryan, {Nathan S.} and Brendan Lee",
note = "Funding Information: This work was supported by the US National Institutes of Health (DK54450, RR19453, RR00188, GM90310 to B.L., GM07526 and DK081735 to A.E., HL75511 to J.L.A., RR024173 to J.C.M. and DK37175 to W.E.M.). We acknowledge and thank the clinical efforts of M. Mullins, S. Carter, A. Tran, J. Stuff, W. Martinek and the Texas Children{\textquoteright}s Hospital General Clinical Research Center nursing staff. The mutated human ASL–encoding plasmids were kindly provided by L. Salviati from the Department of Pediatrics, University of Padova, Padova, Italy. We thank the families of the subjects for their kind participation. We greatly appreciate the technical contributions of M. Jiang, E. Munivez, B. Dawson, G. Sule and J. Zhang. Funding Information: We thank L. Castillo for helpful discussions. Figures were produced using Servier Medical Art. A.E., S.C.S.N. and O.A.S. are awardees of the National Urea Cycle Disorder Foundation Research Fellowship. O.A.S. is an awardee of the O{\textquoteright}Malley Fellowship of the Urea Cycle Disorders Rare Disease Clinical Research Network. N.S.B. is supported by the American Heart Association-National 0735042N. P.M.C. is an awardee of the Canadian Institute of Health Research clinician-scientist training award.",
year = "2011",
month = dec,
doi = "10.1038/nm.2544",
language = "English (US)",
volume = "17",
pages = "1619--1626",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",
}