{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n GTP cyclohydrolase I (GCH1) is the rate‐limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for several enzymes including nitric oxide synthases (NOS) and aromatic amino acid hydroxylases. Adequate BH4 levels are critical for dopamine production in nigrostriatal neurons, and loss‐of‐function mutations or deletions in GCH1 lead to dopa‐responsive dystonia and related movement disorders—with clinical presentations that may include parkinsonism and paroxysmal exercise‐induced dystonia"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In endothelial cells, BH4 generated via GCH1 is required to maintain proper coupling of endothelial NOS (eNOS) so that nitric oxide (NO) is produced rather than superoxide. This function is essential for preserving vascular tone, limiting oxidative stress, and reducing inflammatory vascular remodeling. Indeed, inflammatory mediators or conditions such as high glucose or nicotine can suppress GCH1 expression, thereby reducing BH4 levels and leading to eNOS uncoupling and endothelial dysfunction"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "19"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic variations in GCH1 also influence pain sensitivity. Several studies have demonstrated that specific single nucleotide polymorphisms and haplotypes in GCH1 are associated with diminished BH4 upregulation upon sensitization, thereby conferring protection against persistent or inflammatory pain"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, GCH1 expression and activity are finely regulated by multiple stimuli. For example, common genetic variants can alter basal NO secretion and autonomic function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", while inflammatory, shear‐stress, and neurohumoral signals modulate GCH1 by affecting its transcription, post‐translational modifications, and interactions with regulatory proteins"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "29"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these diverse studies underscore the pleiotropic functions of GCH1 in modulating neurotransmitter biosynthesis, vascular homeostasis, and nociceptive signaling. The enzyme’s role in maintaining BH4 availability is a central node in the regulation of both neuronal and endothelial function, thereby representing a promising therapeutic target for treating neurological disorders such as dopa‐responsive dystonia, as well as cardiovascular and pain syndromes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Zimprich, M Grabowski, F Asmus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng709"}], "href": "https://doi.org/10.1038/ng709"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11528394"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11528394"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Niccolò E Mencacci, Ioannis U Isaias, Martin M Reich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Parkinson's disease in GTP cyclohydrolase 1 mutation carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awu179"}], "href": "https://doi.org/10.1093/brain/awu179"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24993959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24993959"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "I Trender-Gerhard, M G Sweeney, P Schwingenschuh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurol Neurosurg Psychiatry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jnnp.2008.155861"}], "href": "https://doi.org/10.1136/jnnp.2008.155861"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19332422"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19332422"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Fabienne Clot, David Grabli, Cécile Cazeneuve, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awp084"}], "href": "https://doi.org/10.1093/brain/awp084"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19491146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19491146"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "C Wider, S Melquist, M Hauf, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/01.wnl.0000275527.35752.c5"}], "href": "https://doi.org/10.1212/01.wnl.0000275527.35752.c5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17804835"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17804835"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Russell C Dale, Anna Melchers, Victor S C Fung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Med Child Neurol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1469-8749.2010.03619.x"}], "href": "https://doi.org/10.1111/j.1469-8749.2010.03619.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20187889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20187889"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Masaya Segawa "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal dominant GTP cyclohydrolase I (AD GCH 1) deficiency (Segawa disease, dystonia 5; DYT 5)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chang Gung Med J (2009)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19292934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19292934"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Jianfeng Xiao, Robert W Bastian, Joel S Perlmutter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-throughput mutational analysis of TOR1A in primary dystonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2350-10-24"}], "href": "https://doi.org/10.1186/1471-2350-10-24"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19284587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19284587"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Brian R Clapp, Gideon M Hirschfield, Clare Storry, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.CIR.0000159336.31613.31"}], "href": "https://doi.org/10.1161/01.CIR.0000159336.31613.31"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15795363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15795363"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mark J Crabtree, Amy L Tatham, Yasir Al-Wakeel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M805403200"}], "href": "https://doi.org/10.1074/jbc.M805403200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19011239"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19011239"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Travis W Hein, Uma Singh, Jeannette Vasquez-Vivar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human C-reactive protein induces endothelial dysfunction and uncoupling of eNOS in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2009.02.002"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2009.02.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19268941"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19268941"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Uma Singh, Sridevi Devaraj, Jeannette Vasquez-Vivar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Cardiol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yjmcc.2007.08.015"}], "href": "https://doi.org/10.1016/j.yjmcc.2007.08.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17942113"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17942113"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Shuangxi Wang, Jian Xu, Ping Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acute inhibition of guanosine triphosphate cyclohydrolase 1 uncouples endothelial nitric oxide synthase and elevates blood pressure."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hypertension (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/HYPERTENSIONAHA.108.112094"}], "href": "https://doi.org/10.1161/HYPERTENSIONAHA.108.112094"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18645049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18645049"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Rui Wei, Shifeng Ma, Chen Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Endocrinol Metab (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpendo.00400.2015"}], "href": "https://doi.org/10.1152/ajpendo.00400.2015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27072494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27072494"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "An L Moens, Jordan S Leyton-Mange, Xiaolin Niu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Cardiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yjmcc.2009.06.005"}], "href": "https://doi.org/10.1016/j.yjmcc.2009.06.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19766235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19766235"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Manasi Nandi, Alyson Miller, Raymond Stidwill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.CIR.0000163268.32638.F4"}], "href": "https://doi.org/10.1161/01.CIR.0000163268.32638.F4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15824199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15824199"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Jingyuan Li, Shangming Liu, Guangqing Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nicotine induces endothelial dysfunction and promotes atherosclerosis via GTPCH1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.13812"}], "href": "https://doi.org/10.1111/jcmm.13812"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30091833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30091833"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Zhi-Wei Zhou, Xiao-Liang Xie, Shu-Feng Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of reversal of high glucose-induced endothelial nitric oxide synthase uncoupling by tanshinone IIA in human endothelial cell line EA.hy926."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2012.09.051"}], "href": "https://doi.org/10.1016/j.ejphar.2012.09.051"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23063542"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23063542"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ricardo Carnicer, Ashley B Hale, Silvia Suffredini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.112.274464"}], "href": "https://doi.org/10.1161/CIRCRESAHA.112.274464"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22798524"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22798524"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Ziad A Ali, Christina A Bursill, Gillian Douglas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CCR2-mediated antiinflammatory effects of endothelial tetrahydrobiopterin inhibit vascular injury-induced accelerated atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.107.753558"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.107.753558"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18824773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18824773"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Irmgard Tegeder, Jan Adolph, Helmut Schmidt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pain (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejpain.2008.02.004"}], "href": "https://doi.org/10.1016/j.ejpain.2008.02.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18374612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18374612"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Hyungsuk Kim, Raymond A Dionne "}, {"type": "b", "children": [{"type": "t", "text": "Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Pain (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1744-8069-3-6"}], "href": "https://doi.org/10.1186/1744-8069-3-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17343757"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17343757"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Jörn Lötsch, Pål Klepstad, Alexandra Doehring, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A GTP cyclohydrolase 1 genetic variant delays cancer pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pain (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pain.2009.10.021"}], "href": "https://doi.org/10.1016/j.pain.2009.10.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19959292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19959292"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Jörn Lötsch, Inna Belfer, Anja Kirchhof, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1373/clinchem.2006.082883"}], "href": "https://doi.org/10.1373/clinchem.2006.082883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17363416"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17363416"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Lian Zhang, Fangwen Rao, Kuixing Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI31093"}], "href": "https://doi.org/10.1172/JCI31093"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17717598"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17717598"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Charalambos Antoniades, Colin Cunnington, Alexis Antonopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.111.029272"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.111.029272"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21969008"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21969008"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Li Li, Amir Rezvan, John C Salerno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.109.210658"}], "href": "https://doi.org/10.1161/CIRCRESAHA.109.210658"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19926872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19926872"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "S Dos Santos, A-I Delattre, F De Longueville, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene expression profiling of LPS-stimulated murine macrophages and role of the NF-kappaB and PI3K/mTOR signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann N Y Acad Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1196/annals.1397.071"}], "href": "https://doi.org/10.1196/annals.1397.071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17405917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17405917"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Kouhei Sakai, Harumi Suzuki, Hiroyo Oda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: critical dimerization of inducible nitric-oxide synthase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M601896200"}], "href": "https://doi.org/10.1074/jbc.M601896200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16636057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16636057"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Jianhai Du, Na Wei, Tongju Guan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of CDKS by roscovitine suppressed LPS-induced *NO production through inhibiting NFkappaB activation and BH4 biosynthesis in macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00138.2009"}], "href": "https://doi.org/10.1152/ajpcell.00138.2009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19553566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19553566"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Ciprian B Anea, Bo Cheng, Shruti Sharma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.111.261750"}], "href": "https://doi.org/10.1161/CIRCRESAHA.111.261750"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22912383"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22912383"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Christopher S Rabender, Asim Alam, Gobalakrishnan Sundaresan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-15-0057-T"}], "href": "https://doi.org/10.1158/1541-7786.MCR-15-0057-T"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25724429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25724429"}]}]}]}