{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:00:02Z","timestamp":1790913602618,"version":"4.1.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>Drug-eluting stent delivery of mTORC1 (mechanistic target of rapamycin complex 1) inhibitors is highly effective in preventing intimal hyperplasia after coronary revascularization, but adverse effects limit their use for systemic vascular disease. Understanding the mechanism of action may lead to new treatment strategies. We have shown that rapamycin promotes vascular smooth muscle cell differentiation in an AKT2-dependent manner in vitro. Here, we investigate the roles of AKT (protein kinase B) isoforms in intimal hyperplasia.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              We found that germ-line\u2013specific or smooth muscle\u2013specific deletion of\n              <jats:italic>Akt2<\/jats:italic>\n              resulted in more severe intimal hyperplasia compared with control mice after arterial denudation injury. Conversely, smooth muscle\u2013specific\n              <jats:italic>Akt1<\/jats:italic>\n              knockout prevented intimal hyperplasia, whereas germ-line\n              <jats:italic>Akt1<\/jats:italic>\n              deletion caused severe thrombosis. Notably, rapamycin prevented intimal hyperplasia in wild-type mice but had no therapeutic benefit in\n              <jats:italic>Akt2<\/jats:italic>\n              knockouts. We identified opposing roles for AKT1 and AKT2 isoforms in smooth muscle cell proliferation, migration, differentiation, and rapamycin response in vitro. Mechanistically, rapamycin induced\n              <jats:italic>MYOCD<\/jats:italic>\n              (myocardin) mRNA expression. This was mediated by AKT2 phosphorylation and nuclear exclusion of FOXO4 (forkhead box O4), inhibiting its binding to the\n              <jats:italic>MYOCD<\/jats:italic>\n              promoter.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Our data reveal opposing roles for AKT isoforms in smooth muscle cell remodeling. AKT2 is required for rapamycin\u2019s therapeutic inhibition of intimal hyperplasia, likely mediated in part through AKT2-specific regulation of MYOCD via FOXO4. Because AKT2 signaling is impaired in diabetes mellitus, this work has important implications for rapamycin therapy, particularly in diabetic patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.117.310053","type":"journal-article","created":{"date-parts":[[2017,10,13]],"date-time":"2017-10-13T00:10:27Z","timestamp":1507853427000},"page":"2311-2321","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response"],"prefix":"10.1161","volume":"37","author":[{"given":"Yu","family":"Jin","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xie","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison C.","family":"Ostriker","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinbo","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjing","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen L.","family":"Leslie","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waiho","family":"Tang","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Du","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingdi","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Sessa","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hwa","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yu","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Martin","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (Y.J., Y.X., A.C.O., K.L.L., W.T., J.D., S.H.L., Y.W., J.H., K.A.M.) and Department of Pharmacology (Y.J., Y.X., A.C.O., M.Y.L., K.L.L., W.C.S., K.A.M.), Yale University, New Haven, CT; Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT (X.Z.); Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, University of..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-012110-142315"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa035071"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCINTERVENTIONS.113.000415"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.009"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209087"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2015.03.003"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24726"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1307"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.10.007"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904073106"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10960"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/hq0701.092104"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.76.3.412"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119038"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00201.2003"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703914200"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.002887"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.01.001"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-14-0330"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.292.5522.1728"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.06.002"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.29.20140151"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005482"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.300735"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305895"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600788200"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.17.3.1129"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00043-X"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01748-06"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2005.05.017"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.216804"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0058746"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.01.007"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.202747"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.79.6.1374"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.24.2967"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100462200"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200505087"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.4161\/cam.5.3.15790"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.12.001"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.618421"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.108.189316"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI20267"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.196394"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304284"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt252"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-262097"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.11.025"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E09-09-0795"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.12.018"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705842105"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411585200"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCINTERVENTIONS.115.003255"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.117.310053","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T22:54:26Z","timestamp":1715554466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.117.310053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12]]},"references-count":53,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1161\/ATVBAHA.117.310053"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.117.310053","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12]]},"assertion":[{"value":"2017-04-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}