{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T14:35:13Z","timestamp":1781102113110,"version":"3.54.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"14","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,4,7]]},"abstract":"<jats:p>\n                    Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT\n                    <jats:sub>1<\/jats:sub>\n                    Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G\n                    <jats:sub>q\/11<\/jats:sub>\n                    -proteins, to which the AT\n                    <jats:sub>1<\/jats:sub>\n                    R normally couples. Here, we describe a novel signaling pathway underlying this AT\n                    <jats:sub>1<\/jats:sub>\n                    R-dependent aldosterone production mediated by \u03b2-arrestin-1 (\u03b2arr1), a universal heptahelical receptor adapter\/scaffolding protein. This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein, a steroid transport protein regulating aldosterone biosynthesis in AZG cells. Also, this \u03b2arr1-mediated pathway appears capable of promoting aldosterone turnover independently of G protein activation, because treatment of AZG cells with SII, an AngII analog that induces \u03b2arr, but not G protein coupling to the AT\n                    <jats:sub>1<\/jats:sub>\n                    R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal \u03b2arr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a \u03b2arr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical \u03b2arr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal \u03b2arr1 activity on AT\n                    <jats:sub>1<\/jats:sub>\n                    Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0811706106","type":"journal-article","created":{"date-parts":[[2009,3,16]],"date-time":"2009-03-16T21:38:29Z","timestamp":1237239509000},"page":"5825-5830","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":100,"title":["An adrenal \u03b2-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo"],"prefix":"10.1073","volume":"106","author":[{"given":"Anastasios","family":"Lymperopoulos","sequence":"first","affiliation":[{"name":"Center for Translational Medicine and"},{"name":"George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Rengo","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine and"},{"name":"George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Zincarelli","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Soltys","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Koch","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine and"},{"name":"George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,4,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra000050"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.06017"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1042\/CS20070123"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01307.2005"},{"key":"e_1_3_3_5_2","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S0031-6997(25)06811-5","article-title":"Role of calcium and other mediators in aldosterone secretion from the adrenal glomerulosa cells","volume":"46","author":"Ganguly A","year":"1994","unstructured":"A Ganguly, JS Davis, Role of calcium and other mediators in aldosterone secretion from the adrenal glomerulosa cells. Pharmacol Rev 46, 417\u2013447 (1994).","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_6_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0031-6997(24)01458-3","article-title":"International union of pharmacology. XXIII. The angiotensin II receptors","volume":"52","author":"De Gasparo M","year":"2000","unstructured":"M De Gasparo, KJ Catt, T Inagami, JW Wright, T Unger, International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52, 415\u2013472 (2000).","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.11.007"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109237"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1553"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2003.12.020"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.133.4.8404594"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mt.6300371"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206595200"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5247.363"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.51.32507"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1134562"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001553200"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)49643-9"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)81646-0"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300443200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2007.06.006"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.041604898"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706892200"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208109200"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.09.011"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03338"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.22.2.0428"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.11.7039"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300573200"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25330"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705869200"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/16.suppl_N.103"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1993.tb03901.x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000025904.23047.27"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.138.2.5032"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0811706106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T07:50:58Z","timestamp":1739001058000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0811706106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,4,7]]},"references-count":35,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2009,4,7]]}},"alternative-id":["10.1073\/pnas.0811706106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0811706106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,4,7]]},"assertion":[{"value":"2008-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-04-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}