{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T10:17:28Z","timestamp":1771496248077,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,7,1]],"date-time":"2011-07-01T00:00:00Z","timestamp":1309478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH4) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein\u201390 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5\u2032-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH4, may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90\u2013GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH4 concentrations. We also found in vivo that Hsp90\/GCH1 interactions are decreased, whereas GCH1\u2013Hsp70 and GCH1\u2013CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90\u2013GCH1 interactions and increased both BH4 and NOx concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH4 concentrations, secondary to the disruption of Hsp90\u2013GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.<\/jats:p>","DOI":"10.1165\/rcmb.2009-0467oc","type":"journal-article","created":{"date-parts":[[2010,9,24]],"date-time":"2010-09-24T23:32:18Z","timestamp":1285371138000},"page":"163-171","source":"Crossref","is-referenced-by-count":26,"title":["C-Terminus of Heat Shock Protein 70\u2013Interacting Protein\u2013Dependent GTP Cyclohydrolase I Degradation in Lambs with Increased Pulmonary Blood Flow"],"prefix":"10.1093","volume":"45","author":[{"given":"Xutong","family":"Sun","sequence":"first","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohrab","family":"Fratz","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiology and Congenital Heart Disease and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Sharma","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yali","family":"Hou","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruslan","family":"Rafikov","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjiv","family":"Kumar","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imran","family":"Rehmani","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Tian","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Smith","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Section of Cardiac Surgery, German Heart Center Munich, Technical University Munich, Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Reiser","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiology and Congenital Heart Disease and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Naumann","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiology and Congenital Heart Disease and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Haag","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiology and Congenital Heart Disease and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Hess","sequence":"additional","affiliation":[{"name":"Section of Pediatric Cardiology and Congenital Heart Disease and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Catravas","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cam","family":"Patterson","sequence":"additional","affiliation":[{"name":"Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffery R.","family":"Fineman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M.","family":"Black","sequence":"additional","affiliation":[{"name":"Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2011,7,1]]},"reference":[{"key":"2026021904073147100_bib1","doi-asserted-by":"crossref","first-page":"C1407","DOI":"10.1152\/ajpcell.00384.2007","volume":"294","year":"2008","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026021904073147100_bib2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0065-2423(09)48003-X","volume":"48","year":"2009","journal-title":"Adv Clin Chem"},{"key":"2026021904073147100_bib3","first-page":"1467","volume":"41","year":"2003","journal-title":"Clin Chem Lab Med"},{"key":"2026021904073147100_bib4","doi-asserted-by":"crossref","first-page":"2842S","DOI":"10.1093\/jn\/134.10.2842S","volume":"134","year":"2004","journal-title":"J Nutr"},{"key":"2026021904073147100_bib5","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/01.CIR.0000051466.00227.13","volume":"107","year":"2003","journal-title":"Circulation"},{"key":"2026021904073147100_bib6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1042\/CS20070108","volume":"113","year":"2007","journal-title":"Clin Sci (Lond)"},{"key":"2026021904073147100_bib7","first-page":"185","volume":"378","year":"1997","journal-title":"Biol Chem"},{"key":"2026021904073147100_bib8","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1111\/j.1471-4159.2006.03836.x","volume":"97","year":"2006","journal-title":"J Neurochem"},{"key":"2026021904073147100_bib9","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1161\/ATVBAHA.107.153742","volume":"27","year":"2007","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026021904073147100_bib10","first-page":"1","volume":"92","year":"1995","journal-title":"Circulation"},{"key":"2026021904073147100_bib11","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1161\/01.CIR.0000027109.14149.67","volume":"106","year":"2002","journal-title":"Circulation"},{"key":"2026021904073147100_bib12","doi-asserted-by":"crossref","first-page":"L984","DOI":"10.1152\/ajplung.00224.2003","volume":"286","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib13","doi-asserted-by":"crossref","first-page":"L309","DOI":"10.1152\/ajplung.90538.2008","volume":"297","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.devbrainres.2005.02.008","volume":"156","year":"2005","journal-title":"Brain Res Dev Brain Res"},{"key":"2026021904073147100_bib15","doi-asserted-by":"crossref","first-page":"L1444","DOI":"10.1152\/ajplung.00175.2007","volume":"293","year":"2007","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1254\/jphs.08322FP","volume":"111","year":"2009","journal-title":"J Pharmacol Sci"},{"key":"2026021904073147100_bib17","doi-asserted-by":"crossref","first-page":"12847","DOI":"10.1073\/pnas.202365899","volume":"99","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021904073147100_bib18","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1115\/1.3138276","volume":"103","year":"1981","journal-title":"J Biomech Eng"},{"key":"2026021904073147100_bib19","doi-asserted-by":"crossref","first-page":"L490","DOI":"10.1152\/ajplung.2001.281.2.L490","volume":"281","year":"2001","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib20","doi-asserted-by":"crossref","first-page":"L46","DOI":"10.1152\/ajplung.00247.2007","volume":"294","year":"2008","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib21","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1177\/153537020322800201","volume":"228","year":"2003","journal-title":"Exp Biol Med (Maywood)"},{"key":"2026021904073147100_bib22","doi-asserted-by":"crossref","first-page":"9002","DOI":"10.1074\/jbc.272.14.9002","volume":"272","year":"1997","journal-title":"J Biol Chem"},{"key":"2026021904073147100_bib23","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.biochem.67.1.425","volume":"67","year":"1998","journal-title":"Annu Rev Biochem"},{"key":"2026021904073147100_bib24","doi-asserted-by":"crossref","first-page":"L960","DOI":"10.1152\/ajplung.00449.2006","volume":"293","year":"2007","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904073147100_bib25","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1161\/CIRCULATIONAHA.106.684795","volume":"116","year":"2007","journal-title":"Circulation"},{"key":"2026021904073147100_bib26","doi-asserted-by":"crossref","first-page":"49332","DOI":"10.1074\/jbc.M304738200","volume":"278","year":"2003","journal-title":"J Biol Chem"},{"key":"2026021904073147100_bib27","doi-asserted-by":"crossref","first-page":"H3080","DOI":"10.1152\/ajpheart.00579.2007","volume":"293","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026021904073147100_bib28","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1161\/01.RES.0000016837.26733.BE","volume":"90","year":"2002","journal-title":"Circ Res"},{"key":"2026021904073147100_bib29","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1379\/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2","volume":"3","year":"1998","journal-title":"Cell Stress Chaperones"},{"key":"2026021904073147100_bib30","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1152\/physrev.00027.2001","volume":"82","year":"2002","journal-title":"Physiol Rev"},{"key":"2026021904073147100_bib31","doi-asserted-by":"crossref","first-page":"52970","DOI":"10.1074\/jbc.M406926200","volume":"279","year":"2004","journal-title":"J Biol Chem"},{"key":"2026021904073147100_bib32","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1161\/01.ATV.0000115637.48689.77","volume":"24","year":"2004","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2026021904073147100_bib33","doi-asserted-by":"crossref","first-page":"28128","DOI":"10.1074\/jbc.M109.041483","volume":"284","year":"2009","journal-title":"J Biol Chem"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/45\/1\/163\/66899692\/ajrcmb_45_1_163.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/45\/1\/163\/66899692\/ajrcmb_45_1_163.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:07:47Z","timestamp":1771492067000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/45\/1\/163\/8474640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,1]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2011,7,1]]},"published-print":{"date-parts":[[2011,7,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2009-0467oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,7]]},"published":{"date-parts":[[2011,7,1]]}}}