{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:15:35Z","timestamp":1790014535764,"version":"4.0.1"},"reference-count":96,"publisher":"American Physiological Society","issue":"4","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["T32HL094300"],"award-info":[{"award-number":["T32HL094300"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["1F32HL126311"],"award-info":[{"award-number":["1F32HL126311"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["R21HL1139181"],"award-info":[{"award-number":["R21HL1139181"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI)","doi-asserted-by":"publisher","award":["R01HL114784"],"award-info":[{"award-number":["R01HL114784"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association (AHA)","doi-asserted-by":"publisher","award":["15POST22740017"],"award-info":[{"award-number":["15POST22740017"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2017,10,1]]},"abstract":"<jats:p>Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, G<jats:sub>q<\/jats:sub>-mediated signaling was selectively enhanced in CFs by G\u03b1<jats:sub>q<\/jats:sub>adenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca<jats:sup>2+<\/jats:sup>-sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMP<jats:sub>CF<\/jats:sub>). Enhanced G<jats:sub>q<\/jats:sub>signaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active G\u03b1<jats:sub>q<\/jats:sub>in CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca<jats:sup>2+<\/jats:sup>transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization-induced automaticity. Constitutive G<jats:sub>q<\/jats:sub>activation in CFs also depolarized RMP<jats:sub>CF<\/jats:sub>from \u201333 to \u221220 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMP<jats:sub>CF<\/jats:sub>and increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca<jats:sup>2+<\/jats:sup>transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced G<jats:sub>q<\/jats:sub>signaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity.<\/jats:p>","DOI":"10.1152\/ajpheart.00181.2017","type":"journal-article","created":{"date-parts":[[2017,7,15]],"date-time":"2017-07-15T01:00:27Z","timestamp":1500080427000},"page":"H810-H827","source":"Crossref","is-referenced-by-count":20,"title":["G<sub>q<\/sub>-activated fibroblasts induce cardiomyocyte action potential prolongation and automaticity in a three-dimensional microtissue environment"],"prefix":"10.1152","volume":"313","author":[{"given":"C. M.","family":"Kofron","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"King","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Xie","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Feng","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Park","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z.","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.-R.","family":"Choi","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U.","family":"Mende","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.2012.707181"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.10140"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.303794"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccep.2010.10.012"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr351"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.079509"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00514.2007"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.06.042"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/10763270360728152"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.01.027"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1215"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.135038"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01220.2004"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.15.8121"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.10.019"},{"key":"B16","doi-asserted-by":"crossref","first-page":"18263","DOI":"10.1016\/S0021-9258(19)36952-2","volume":"267","author":"De Vivo M","year":"1992","journal-title":"J Biol Chem"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00743.2011"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116995"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c140053"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/clc.4960190409"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-9-46"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1021\/pr0700596"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000089258.40661.0C"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(70)90339-3"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.89"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu227"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(98)00121-7"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1159\/000080338"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr189"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.02.004"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055400"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01298.2007"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eum207"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2002.88.4.1893"},{"key":"B35","first-page":"9","volume":"92","author":"Janse MJ","year":"1999","journal-title":"Arch Mal Coeur Vaiss"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.08.018"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00205.2016"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00775-7"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00240.2001"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/27.12.2125"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308643"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055391"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2004.04.022"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1998.0673"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1113\/JP273100"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2005.06.096"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.12.024"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1994.sp003819"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.305381"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007307"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.2.12.1081"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.68.6.1501"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.101410"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/srep26744"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2015.12.006"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1007\/s10544-005-6070-2"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.10.005"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.969329"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13893"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000214537.44195.a3"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.160549"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072950"},{"key":"B63","first-page":"H80","volume":"277","author":"Nuss HB","year":"1999","journal-title":"Am J Physiol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.01.010"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2236"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.91531.2007"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvp164"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.07.016"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.9.4077"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.10.007"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611184114"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.110.957647"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1007\/BF00585633"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1992.263.5.C959"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.11.014"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-009-9667-4"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1159\/000272316"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.104.054429"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1038\/srep40985"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00887.2009"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1089\/ten.teb.2014.0383"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00038.2012"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.015057"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.11.025"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0b013e31820cda19"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.227421"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.88.6.2849"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.08.003"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00341.2009"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.06.042"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq329"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00026.2011"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.carpath.2009.12.002"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308139"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0144979"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00181.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:49:24Z","timestamp":1659228564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00181.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,1]]},"references-count":96,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,10,1]]}},"alternative-id":["10.1152\/ajpheart.00181.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00181.2017","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,1]]}}}