{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:19:43Z","timestamp":1788866383951,"version":"build-2803163510"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,1,7]],"date-time":"2015-01-07T00:00:00Z","timestamp":1420588800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Chinese National Programme on Key Basic Research","award":["2012CB524900"],"award-info":[{"award-number":["2012CB524900"]}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2015,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>G protein\u2010regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (<jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content>), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac\u2010specific knockout of <jats:italic><jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content><\/jats:italic> in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased <jats:styled-content style=\"fixed-case\">mTORC1<\/jats:styled-content> signalling pathway after <jats:italic><jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content><\/jats:italic> deletion. Protein farnesylation or <jats:styled-content style=\"fixed-case\">mTORC1<\/jats:styled-content> inhibition blocked <jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content> knockdown\u2010induced <jats:styled-content style=\"fixed-case\">mTORC1<\/jats:styled-content> activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy <jats:italic>in vivo<\/jats:italic>, demonstrating a central role of the <jats:styled-content style=\"fixed-case\">FPP<\/jats:styled-content>\u2013Rheb\u2013<jats:styled-content style=\"fixed-case\">mTORC1<\/jats:styled-content> axis for <jats:italic><jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content><\/jats:italic> deficiency\u2010induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, <jats:styled-content style=\"fixed-case\">GGPPS<\/jats:styled-content> was down\u2010regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (<jats:styled-content style=\"fixed-case\">TAC<\/jats:styled-content>) and in failing human hearts. Moreover, <jats:styled-content style=\"fixed-case\">HPLC\u2013MS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MS<\/jats:styled-content> detection revealed that the myocardial farnesyl diphosphate (<jats:styled-content style=\"fixed-case\">FPP<\/jats:styled-content>):geranylgeranyl diphosphate (<jats:styled-content style=\"fixed-case\">GGPP<\/jats:styled-content>) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy. Copyright \u00a9 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4480","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T01:09:25Z","timestamp":1415668165000},"page":"672-685","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb\u2013<scp>mTORC1<\/scp> signalling and leads to chronic heart failure"],"prefix":"10.1002","volume":"235","author":[{"given":"Na","family":"Xu","sequence":"first","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Guan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology College of Life Science, Nanjing Normal University  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Reproductive Biology Institute of Zoology\/Chinese Academy of Sciences  Beijing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Cardiology Affiliated Drum Tower Hospital of Nanjing University Medical School  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei\u2010Yan","family":"Pan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology College of Life Science, Nanjing Normal University  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning\u2010Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Biomedical Research Laboratory Shimadzu (China) Co. Ltd  Shanghai People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics First Affiliated Hospital with Nanjing Medical University  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong\u2010Zhou","family":"Yang","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Affiliated Drum Tower Hospital of Nanjing University Medical School  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao\u2010Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Ministry of Education Key Laboratory of Model Animals for Disease Study Model Animal Research Centre and Medical School of Nanjing University, National Resource Centre for Mutant Mice  Nanjing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,7]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1983"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6842"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8497"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.39.23173"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.07.016"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7716512"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2741\/2401"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2221"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2004.11.001"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1127704"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.08.033"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs347"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.2310\/6650.2004.04015"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13350"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1734-1140(11)70601-6"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e32833f0fc7"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20121806"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.08.056"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/00041433-199804000-00004"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)32159-3"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0603615103"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-6658-2_10"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.190165"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.359"},{"key":"e_1_2_7_26_1","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J","year":"2001"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2008.04.021"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.423640"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E10-05-0454"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300226200"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3025"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.02.012"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62839"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.hjh.0000388492.73954.0b"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01354.2006"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000183880.49270.f9"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2011.01.023"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050960"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44371"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005262"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00059.2009"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.47.120505.105359"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000057979.36322.88"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.057273"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq570"},{"key":"e_1_2_7_46_1","article-title":"MTORC1 regulates cardiac function and myocyte survival through 4E\u2010BP1 inhibition in mice","volume":"120","author":"Zhang D","journal-title":"J Clin Invest"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801510200"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00338.2010"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.005"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.183087"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608791103"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvs013"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000257913.42552.23"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4480","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4480","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4480","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:53:21Z","timestamp":1760954001000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,7]]},"references-count":52,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,4]]}},"alternative-id":["10.1002\/path.4480"],"URL":"https:\/\/doi.org\/10.1002\/path.4480","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,7]]},"assertion":[{"value":"2014-07-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-11-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-01-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}