{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:11:06Z","timestamp":1778645466176,"version":"3.51.4"},"reference-count":48,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,4,15]],"date-time":"2018-04-15T00:00:00Z","timestamp":1523750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81270237"],"award-info":[{"award-number":["81270237"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pacing Clinical Electrophis"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background\/aims<\/jats:title><jats:p>Cardiac autonomic nerve remodeling (ANR) is an important mechanism of atrial fibrillation (AF). GTP cyclohydrolase I, encoded by GCH1, is the rate\u2010limiting enzyme in <jats:italic>de novo<\/jats:italic> synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthesis. Previous studies reported that increased BH4 and NO content negatively regulated nerve regeneration. This study investigated the effects of GCH1 on ANR via BH4 pathway, regulated by microRNA\u2010206 (miR\u2010206).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>In canines, atrial tachypacing (A\u2010TP), together with miR\u2010206 overexpression, increased PGP9.5 level and inhibited GCH1 expression by quantitative real\u2010time polymerase chain reaction and western blot analysis. GCH1 was validated to be a direct target of miR\u2010206 by luciferase assays. Meanwhile, miR\u2010206 overexpression by lentiviruses infection into right superior pulmonary vein fat pad decreased GCH1 expression to \u223c40% and further reduced BH4 and NO content compared with the control canines. After infection of GCH1 overexpression lentiviruses for two weeks, atrial effective refractory period was increased compared with the control group (105.8 \u00b1 1.537\u00a0ms vs 99.17 \u00b1 2.007\u00a0ms, P<jats:italic>\u00a0<\/jats:italic>&lt;\u00a00.05). Moreover, GCH1 overexpression attenuated canines\u2019 atrial PGP9.5 level to \u223c56% of the controls. In myocardial cells, transfection of GCH1 overexpression lentiviruses also decreased PGP9.5 expression to 26% of the control group. In patients, plasma was collected and miR\u2010206 expression was upregulated in AF patients (n\u00a0=\u00a018) than the controls (n\u00a0=\u00a012).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings suggested that GCH1 downregulation exacerbated ANR by decreasing atrial BH4 and NO content modulated by miR\u2010206 in A\u2010TP canines. This indicates that GCH1 may prevent the initiation of AF through inhibiting ANR.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pace.13289","type":"journal-article","created":{"date-parts":[[2018,2,13]],"date-time":"2018-02-13T12:22:38Z","timestamp":1518524558000},"page":"459-471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["GCH1 attenuates cardiac autonomic nervous remodeling in canines with atrial\u2010tachypacing via tetrahydrobiopterin pathway regulated by microRNA\u2010206"],"prefix":"10.1111","volume":"41","author":[{"given":"Jinqiu","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Examination Center Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ximin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linlin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Special Examination Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juanjuan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Medical Research Center Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju","family":"Liu","sequence":"additional","affiliation":[{"name":"Medical Research Center Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4448-0144","authenticated-orcid":false,"given":"Yinglong","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Cardiology Shandong Provincial Qianfoshan Hospital  Jinan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,4,15]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs253"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.958967"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.175463"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.9.3157"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.08.064"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2002.00735.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2015.10.001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10840-005-2492-2"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90529-Y"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33099"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.000598"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep12276"},{"key":"e_1_2_8_14_1","first-page":"cvw177","article-title":"MicroRNA\u2010153 targeting of KCNQ4 contributes to vascular dysfunction in hypertension","author":"Carr G","year":"2016","journal-title":"Cardiovasc Res"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jjcc.2015.12.007"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.03.005"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122674"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.02.015"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.029272"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.753558"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000089082.40285.C3"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.04.032"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-200406000-00015"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.65.3.671"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085639"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.112797"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/pace.12338"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.02.097"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019845"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20150206"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13372"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.09.012"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00253.2003"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.029223"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1159\/000438647"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr087"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1993.1315"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119750"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eur021"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/375068a0"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-22-08809.2001"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920111798357393"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.065144"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs005"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5566"},{"key":"e_1_2_8_46_1","doi-asserted-by":"crossref","first-page":"e003208","DOI":"10.1161\/JAHA.116.003208","article-title":"Tetrahydrobiopterin protects against hypertrophic heart disease independent of myocardial nitric oxide synthase coupling","volume":"4","author":"Hashimoto T","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.719377"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000054659.72231.A1"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41127"}],"container-title":["Pacing and Clinical Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fpace.13289","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/pace.13289","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T23:47:16Z","timestamp":1695512836000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/pace.13289"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,15]]},"references-count":48,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,5]]}},"alternative-id":["10.1111\/pace.13289"],"URL":"https:\/\/doi.org\/10.1111\/pace.13289","archive":["Portico"],"relation":{},"ISSN":["0147-8389","1540-8159"],"issn-type":[{"value":"0147-8389","type":"print"},{"value":"1540-8159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,15]]},"assertion":[{"value":"2016-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-01-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}