{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T17:12:12Z","timestamp":1750871532695,"version":"3.37.3"},"reference-count":38,"publisher":"American Physiological Society","issue":"9","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["HL16037;HL70631","HL56687;HL75443"],"award-info":[{"award-number":["HL16037;HL70631","HL56687;HL75443"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Institutional T32","award":["HL007101"],"award-info":[{"award-number":["HL007101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:p> Ang II type 1a receptor (AT<jats:sub>1a<\/jats:sub>R)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). \u03b2-Arrestin2 (\u03b2arr2) is known to mediate AT<jats:sub>1a<\/jats:sub>R-dependent MAPK activation, as well as proproliferative and profibrotic signaling in aortic vascular smooth muscle cells. Therefore, we investigated whether \u03b2arr2-dependent signaling contributes to TAA formation in MFS. We used a murine model of MFS [fibrillin ( Fbn)<jats:sup>C1039G\/+<\/jats:sup>] to generate an MFS murine model in combination with genetic \u03b2arr2 deletion ( Fbn<jats:sup>C1039G\/+<\/jats:sup>\/ \u03b2arr2<jats:sup>\u2212\/\u2212<\/jats:sup>). Fbn<jats:sup>C1039G\/+<\/jats:sup>\/ \u03b2arr2<jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed delayed aortic root dilation compared with Fbn<jats:sup>C1039G\/+<\/jats:sup> mice. The mRNA and protein expression of several mediators of TAA formation, including matrix metalloproteinase (MMP)-2 and -9, was reduced in the aorta of Fbn<jats:sup>C1039G\/+<\/jats:sup>\/ \u03b2arr2<jats:sup>\u2212\/\u2212<\/jats:sup> mice relative to Fbn<jats:sup>C1039G\/+<\/jats:sup> mice. Activation of ERK1\/2 was also decreased in the aortas of Fbn<jats:sup>C1039G\/+<\/jats:sup>\/ \u03b2arr2<jats:sup>\u2212\/\u2212<\/jats:sup> mice compared with Fbn<jats:sup>C1039G\/+<\/jats:sup> animals. Small interfering RNA targeting \u03b2arr2 inhibited angiotensin-stimulated expression of proaneurysmal signaling mediators in primary aortic root smooth muscle cells. Angiotensin-stimulated expression of the proaneurysmal signaling mediators MMP-2 and -9 was inhibited by blockade of ERK1\/2 or the EGF receptor, whereas blockade of the transforming growth factor-\u03b2 receptor had no effect. These results suggest that \u03b2arr2 contributes to TAA formation in MFS by regulating ERK1\/2-dependent expression of proaneurysmal genes and proteins downstream of the AT<jats:sub>1a<\/jats:sub>R. Importantly, this demonstration of the unique signaling mechanism by which \u03b2arr2 contributes to aneurysm formation identifies multiple novel, potential therapeutic targets in MFS. <\/jats:p>","DOI":"10.1152\/ajpheart.00291.2015","type":"journal-article","created":{"date-parts":[[2015,9,14]],"date-time":"2015-09-14T21:50:13Z","timestamp":1442267413000},"page":"H1516-H1527","source":"Crossref","is-referenced-by-count":18,"title":["The role of \u03b2-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome"],"prefix":"10.1152","volume":"309","author":[{"given":"James W.","family":"Wisler","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily M.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Raisch","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard A.","family":"Rockman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"},{"name":"Department of Cell Biology, Duke University Medical Center, Durham, North Carolina;"},{"name":"Department of Molecular Genetics, Duke University Medical Center, Durham, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J.","family":"Lefkowitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, North Carolina;"},{"name":"Department of Biochemistry, Duke University Medical Center, Durham, North Carolina; and"},{"name":"Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808463200"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.262789099"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405878200"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.24.8879"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.88.1.37"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2010.31"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083195"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.157776"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.174367"},{"key":"B10","first-page":"1329","volume":"124","author":"Cook JR","year":"2014","journal-title":"J Clin Invest"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.69.022405.154749"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M710515200"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/352337a0"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2001.281.1.H30"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2009.191"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00617.2005"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/383447a0"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192152"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124287"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192149"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M808176200"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.172338"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.23.15011"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108490200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature10145"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.041604898"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253740"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2012.12.012"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000087660.82721.15"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.2988124"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000165133.84978.E2"},{"key":"B32","first-page":"II331","volume":"98","author":"Segura AM","year":"1998","journal-title":"Circulation"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.280399"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.173005"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000218782.52610.dc"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2007.09.016"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.268268"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00443.x"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00291.2015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T18:33:09Z","timestamp":1567967589000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00291.2015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11]]},"references-count":38,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1152\/ajpheart.00291.2015"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00291.2015","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"type":"print","value":"0363-6135"},{"type":"electronic","value":"1522-1539"}],"subject":[],"published":{"date-parts":[[2015,11]]}}}