{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:49:57Z","timestamp":1790675397439,"version":"4.1.0"},"reference-count":40,"publisher":"Portland Press Ltd.","issue":"23","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,12,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and \u03bc-opioid receptor (\u03bcOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased \u03bcOR and adrenergic receptor \u03b12A (\u03b12A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1\/2T202\/Y204, ribosomal protein S6 kinaseT359\/S363, and nNOSS1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of \u03bcOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. \u03bcOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and \u03bcOR, and \u03b12A-AR and \u03bcOR, heterodimers. Losartan also significantly increased the levels of nNOSS1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and \u03bcOR heterodimers in the NTS, leading to progressive hypertension.<\/jats:p>","DOI":"10.1042\/cs20191005","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T14:01:35Z","timestamp":1574431295000},"page":"2401-2413","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Angiotensin II inhibits DDAH1\u2013nNOS signaling via AT1R and \u03bcOR dimerization to modulate blood pressure control in the central nervous system"],"prefix":"10.1042","volume":"133","author":[{"given":"Gwo-Ching","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan"},{"name":"Department of Anesthesiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzyy-Yue","family":"Wong","sequence":"additional","affiliation":[{"name":"International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Hung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiu-Yi","family":"Ho","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tung-Chen","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yu","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine, Department of Internal Medicine, Kaoshiung Medical University Hospital, Kaoshiung Medical University, Kaohsiung, Taiwan"},{"name":"Division of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Jiunn","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan"},{"name":"Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5997-9247","authenticated-orcid":false,"given":"Pei-Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan"},{"name":"Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"2021113012332474200_B1","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1186\/s12889-018-5806-x","article-title":"The economic burden of cardiovascular disease and hypertension in low- and middle-income countries: a systematic review","volume":"18","author":"Gheorghe","year":"2018","journal-title":"BMC Public Health"},{"key":"2021113012332474200_B2","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1038\/nature02871","article-title":"The functions of animal microRNAs","volume":"431","author":"Ambros","year":"2004","journal-title":"Nature"},{"key":"2021113012332474200_B3","doi-asserted-by":"publisher","first-page":"797","DOI":"10.3390\/ijms17070797","article-title":"Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension","volume":"17","author":"Munoz-Durango","year":"2016","journal-title":"Int. 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