{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T23:57:13Z","timestamp":1772927833123,"version":"3.50.1"},"reference-count":53,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2011,1,25]],"date-time":"2011-01-25T00:00:00Z","timestamp":1295913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2011,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hypertension is a typical modern lifestyle\u2010related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II\u2010mediated pathogenesis are still poorly understood. Here, we show that ANG II\u2010mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II\u2010infusion mouse model (3.0 mg\/kg\/d), we compared IRF3\u2010deficient mice (\n                    <jats:italic>Irf3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>\/Bcl2l12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) with matched wild\u2010type (WT) controls. The development of cardiac fibrosis [3.95\u00b10.62% (WT)\n                    <jats:italic>vs.<\/jats:italic>\n                    1.41\u00b10.46% (\n                    <jats:italic>Irj3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>\/Bcl2l12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    )\n                    <jats:italic>;<\/jats:italic>\n                    P&lt;0.01] and accompanied reduction in left ventricle end\u2010diastolic dimension [2.89 \u00b10.10 mm (WT)\n                    <jats:italic>vs.<\/jats:italic>\n                    3.51\u00b10.15 mm (\n                    <jats:italic>Irf3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    \/\n                    <jats:italic>Bcl2l12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    );\n                    <jats:italic>P<\/jats:italic>\n                    =0.012] are strongly suppressed in\n                    <jats:italic>Irf3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <jats:italic>\/Bcl2l12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension\u2010induced cardiac pathogenesis.\u2014Tsushima, K., Osawa, T., Yanai, H., Nakajima, A., Takaoka, A., Manabe, I., Ohba, Y., Imai, Y., Taniguchi, T., Nagai, R. IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II\u2010induced hypertension.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    25, 1531\u20131543 (2011).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.10-174615","type":"journal-article","created":{"date-parts":[[2011,1,25]],"date-time":"2011-01-25T22:43:31Z","timestamp":1295995411000},"page":"1531-1543","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II\u2010induced hypertension"],"prefix":"10.1096","volume":"25","author":[{"given":"Kensuke","family":"Tsushima","sequence":"first","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"},{"name":"Department of Cardiovascular Medicine Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Osawa","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Yanai","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"},{"name":"Core Research for Evolution Science and Technology Japan Science and Technology Agency Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Takaoka","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Ohba","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology and Signal Transduction Hokkaido University Graduate School of Medicine Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadatsugu","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Immunology Graduate School of Medicine University of Tokyo Tokyo Japan"},{"name":"Core Research for Evolution Science and Technology Japan Science and Technology Agency Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryozo","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine Graduate School of Medicine University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,1,25]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009884820941"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1291\/hypres.28.483"},{"issue":"5","key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0022-2828(89)90778-5","article-title":"Patterns of myocardial fibrosis","volume":"21","author":"Weber K T.","year":"1989","journal-title":"J. Mol. Cell. Cardiol."},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000074041.81728.79"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.2.137"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198706043162301"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199108013250501"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199209033271002"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003128200"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000101921.93016.1C"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012673"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00494-4"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000057810.48709.F6"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.4913"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2007.00720.x"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1081315"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni921"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.08.009"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1900"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00053-4"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310616200"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007790200"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03464"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1934678100"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0402-403"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.9.3941-3947.2000"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.82.4.430"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm738"},{"key":"e_1_2_6_30_1","doi-asserted-by":"crossref","first-page":"12448","DOI":"10.1073\/pnas.0905702106","article-title":"Cell type\u2010dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene","volume":"106","author":"Nakajima A.","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"e_1_2_6_31_1","article-title":"Acetylcholine prevents angiotensin II\u2010induced oxidative stress and apoptosis in H9c2 cells","author":"Liu J. J.","year":"2010","journal-title":"Apoptosis"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0b013e3281532b53"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117824"},{"key":"e_1_2_6_34_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1291\/hypres.18.151","article-title":"Left ventricular geometry and cardiac function in mild to moderate essential hypertension","volume":"18","author":"Lin M.","year":"1995","journal-title":"Hypertens. Res."},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.029"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2005-0239OC"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000165133.84978.E2"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000218782.52610.dc"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2009.74"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000254680.71485.92"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.12.6668"},{"key":"e_1_2_6_42_1","first-page":"263","article-title":"Expression and characterization of mouse angiotensin II type 1a receptor tagging hemagglutinin epitope in cultured cells","volume":"3","author":"Ishida J.","year":"1999","journal-title":"Int. J. Mol. Med."},{"key":"e_1_2_6_43_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S0031-6997(24)01471-6","article-title":"Signal transduction mechanisms mediating the physiological and pathophysiologi\u2010cal actions of angiotensin II in vascular smooth muscle cells","volume":"52","author":"Touyz R. M.","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00413.x"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.7.565"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109221200"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.4.1087"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1347"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06796"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01323"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24178"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1613"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700654"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/47260"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.10-174615","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.10-174615","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.10-174615","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T01:38:25Z","timestamp":1761701905000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.10-174615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1,25]]},"references-count":53,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2011,5]]}},"alternative-id":["10.1096\/fj.10-174615"],"URL":"https:\/\/doi.org\/10.1096\/fj.10-174615","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1,25]]},"assertion":[{"value":"2010-10-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-01-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-01-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}