{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T20:04:29Z","timestamp":1792613069718,"version":"4.5.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,11,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Statins reduce aneurysm growth in mouse models of Marfan syndrome, although the mechanism is unknown. In addition to reducing cholesterol, statins block farnesylation and geranylgeranylation, which participate in membrane\u2010bound G\u2010protein signaling, including Ras. We dissected the prenylation pathway to define the effect of statins on aneurysm reduction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              mice were treated with (1) pravastatin (HMG\u2010CoA [3\u2010hydroxy\u20103\u2010methylglutaryl coenzyme A] reductase inhibitor), (2) manumycin A (\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              ;\n              <jats:styled-content style=\"fixed-case\">FPT<\/jats:styled-content>\n              inhibitor), (3) perillyl alcohol (\n              <jats:styled-content style=\"fixed-case\">GGPT<\/jats:styled-content>\n              1 and \u20102 inhibitor), or (4) vehicle control from age 4 to 8\u00a0weeks and euthanized at 12\u00a0weeks. Histological characterization was performed. Protein analysis was completed on aortic specimens to measure ERK (extracellular signal\u2010regulated kinase) signaling. In vitro\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              aortic smooth muscle cells were utilized to measure Ras\u2010dependent\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              signaling and MMP (matrix metalloproteinase) activity. Pravastatin and\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              significantly reduced aneurysm growth compared with vehicle control (n=8 per group). In contrast,\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              did not significantly decrease aneurysm size. Histology illustrated reduced elastin breakdown in\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              \u2010treated mice compared with vehicle control (n=5 per group). Although elevated in control Marfan mice, both phosphorylated c\u2010Raf and phosphorylated\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              1\/2 were significantly reduced in\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              \u2010treated mice (4\u20135 per group). In vitro smooth muscle cell studies confirmed phosphorylated\n              <jats:styled-content style=\"fixed-case\">cR<\/jats:styled-content>\n              af and phosphorylated\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              1\/2 signaling was elevated in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              smooth muscle cells (n=5 per group).\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              smooth muscle cell Ras\u2010dependent\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              signaling and\n              <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\n              activity were reduced following\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              treatment (n=5 per group). Corroborating in\u00a0vitro findings,\n              <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\n              activity was also decreased in pravastatin\u2010treated mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Aneurysm reduction in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              mice following pravastatin and\n              <jats:styled-content style=\"fixed-case\">MA<\/jats:styled-content>\n              treatment was associated with a decrease in Ras\u2010dependent\n              <jats:styled-content style=\"fixed-case\">ERK<\/jats:styled-content>\n              signaling.\n              <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\n              activity can be reduced by diminishing Ras signaling.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.118.008543","type":"journal-article","created":{"date-parts":[[2018,12,16]],"date-time":"2018-12-16T20:51:35Z","timestamp":1544993495000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["Statins Reduce Thoracic Aortic Aneurysm Growth in Marfan Syndrome Mice via Inhibition of the Ras\u2010Induced ERK (Extracellular Signal\u2010Regulated Kinase) Signaling Pathway"],"prefix":"10.1161","volume":"7","author":[{"given":"Tetsuya","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Arakawa","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Tashima","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitoshi","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiovascular Surgery Iwaki Kyoritsu General Hospital Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grayson","family":"Burdon","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Trojan","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Koyano","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young\u2010Nam","family":"Youn","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Division of Cardiovascular Surgery Severance Cardiovascular Hospital Yonsei University College of Medicine Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiril","family":"Penov","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiac Surgery Heart Center Leipzig University of Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert J.","family":"Pedroza","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Shabazzi","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itai","family":"Palmon","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Noel","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Connolly","sequence":"additional","affiliation":[{"name":"Department of Pathology Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Fischbein","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197204132861502"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67789-6"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192149"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1404731"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199405123301902"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.012187"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2011.06.071"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00247-9"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000068646.76823.AE"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/hq1101.098486"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(02)01857-0"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3255"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/343425a0"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253740"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13257"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304364"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/352337a0"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejvs.2005.12.024"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2008.03.020"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2009.03.028"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2002.123680"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.06.009"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.006"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(97)00151-2"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.11.121"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.016"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.034"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2010.199"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.2174\/1573403X1002140506124902"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.118.008543","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T10:58:30Z","timestamp":1715597910000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.118.008543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,6]]},"references-count":29,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2018,11,6]]}},"alternative-id":["10.1161\/JAHA.118.008543"],"URL":"https:\/\/doi.org\/10.1161\/jaha.118.008543","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,6]]},"assertion":[{"value":"2018-01-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e008543"}}