{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:11:54Z","timestamp":1789747914633,"version":"4.0.1"},"reference-count":75,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFA1104500"],"award-info":[{"award-number":["2022YFA1104500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270703"],"award-info":[{"award-number":["82270703"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370423"],"award-info":[{"award-number":["82370423"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Sustained \u03b2\u2010adrenergic activation induces cardiac fibrosis characterized by excessive deposition of extracellular matrix (ECM). Prostaglandin E\n                    <jats:sub>2<\/jats:sub>\n                    (PGE\n                    <jats:sub>2<\/jats:sub>\n                    ) receptor EP4 is essential for cardiovascular homeostasis. This study aims to investigate the roles of cardiomyocyte (CM) and cardiac fibroblast (CF) EP4 in isoproterenol (ISO)\u2010induced cardiac fibrosis. By crossing the EP4\n                    <jats:sup>f\/f<\/jats:sup>\n                    mice with \u03b1\u2010MyHC\u2010Cre or S100A4\u2010Cre mice, this work obtains the CM\u2010EP4 knockout (EP4\n                    <jats:sup>f\/f<\/jats:sup>\n                    \u2010\u03b1\u2010MyHC\n                    <jats:sup>Cre+<\/jats:sup>\n                    ) or CF\u2010EP4 knockout (EP4\n                    <jats:sup>f\/f<\/jats:sup>\n                    \u2010S100A4\n                    <jats:sup>Cre+<\/jats:sup>\n                    ) mice. The mice of both genders are subcutaneously injected with ISO (5 mg\u00a0kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00a0day\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) for 7 days. Compared to the control mice, both EP4\n                    <jats:sup>f\/f<\/jats:sup>\n                    \u2010\u03b1\u2010MyHC\n                    <jats:sup>Cre+<\/jats:sup>\n                    and EP4\n                    <jats:sup>f\/f<\/jats:sup>\n                    \u2010S100A4\n                    <jats:sup>Cre+<\/jats:sup>\n                    mice show a significant improvement in cardiac diastolic function and fibrosis as assessed by echocardiography and histological staining, respectively. In the CMs, inhibition of EP4 suppresses ISO\u2010induced TGF\u2010\u03b21 expression via blocking the cAMP\/PKA pathway. In the CFs, inhibition of EP4 reversed TGF\u2010\u03b21\u2010triggers production of ECM via preventing the formation of the TGF\u2010\u03b21\/TGF\u2010\u03b2 receptor complex and blocks CF proliferation via suppressing the ERK1\/2 pathway. Furthermore, double knockout of the CM\u2010 and CF\u2010EP4 or administration of EP4 antagonist, grapiprant, markedly improves ISO\u2010induced cardiac diastolic dysfunction and fibrosis. Collectively, this study demonstrates that both CM\u2010EP4 and CF\u2010EP4 contribute to \u03b2\u2010adrenergic activation\u2010induced cardiac fibrosis. Targeting EP4 may offer a novel therapeutic approach for cardiac fibrosis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202413324","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T21:51:02Z","timestamp":1739224262000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting the E Prostanoid Receptor EP4 Mitigates Cardiac Fibrosis Induced by \u03b2\u2010Adrenergic Activation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1198-0932","authenticated-orcid":false,"given":"Hu","family":"Xu","sequence":"first","affiliation":[{"name":"Wuhu Hospital East China Normal University  Shanghai 200241 China"},{"name":"Health Science Center East China Normal University  Shanghai 200241 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhui","family":"Mao","sequence":"additional","affiliation":[{"name":"Health Science Center East China Normal University  Shanghai 200241 China"},{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Wang","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Health Science Center East China Normal University  Shanghai 200241 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Liang","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengfei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Ye","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengting","family":"Hong","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huishu","family":"Shao","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yashuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haonan","family":"Li","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio\u2010Intelligent Manufacturing School of Bioengineering Dalian University of Technology  Dalian 116024 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Nephrology Pudong New District Punan Hospital  Shanghai 200125 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Yang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bio\u2010Intelligent Manufacturing School of Bioengineering Dalian University of Technology  Dalian 116024 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Chen","sequence":"additional","affiliation":[{"name":"Health Science Center East China Normal University  Shanghai 200241 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfei","family":"Guan","sequence":"additional","affiliation":[{"name":"Health Science Center East China Normal University  Shanghai 200241 China"},{"name":"Advanced Institute for Medical Sciences Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4060-2423","authenticated-orcid":false,"given":"Xiaoyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Wuhu Hospital East China Normal University  Shanghai 200241 China"},{"name":"Health Science Center East China Normal University  Shanghai 200241 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.26599\/1671-5411.2023.06.001"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab892"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.28103"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1349-6"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1388378"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42028"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2016.163"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168957"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz318"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-308712"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107624"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.hco.0000245740.85829.4f"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.123.320045"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805806106"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09492-4"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00414-5"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.749739"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102825"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.118.009216","volume":"7","author":"Wu J. M. F.","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14656"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/1324347"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.09.016"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00904.2005"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1536\/ihj.16-200"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14524"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.51183"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)23853-8"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2022.07.012"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2016.2630"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175780"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2019.03.001"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-007-9007-4"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx261"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2017.10.034"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199911000-00003"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.62.1.65"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.035420"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2023.119640"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12958"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04319-w"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2018.03.005"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/now049"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414530200"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2042-7158.2012.01499.x"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01764-w"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.10.006"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.10.013"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/16.suppl_O.107"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-00925-z"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1902119116"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201694660"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e3181a5c84c"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.31496"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.123.066298"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-024-00996-1"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-0299"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c02058"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/vms3.13"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvim.13948"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvp.12349"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/jvp.12983"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119263"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01179-3"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.20.2338"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202303283"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00395.2013"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1613"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319737"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-022-2189-x"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.09.005"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.116000"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024657"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz397"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci200227u"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202413324","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202413324","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202413324","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T15:40:50Z","timestamp":1789746050000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202413324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,7]]},"references-count":75,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/advs.202413324"],"URL":"https:\/\/doi.org\/10.1002\/advs.202413324","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,7]]},"assertion":[{"value":"2024-10-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2413324"}}