{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:02:22Z","timestamp":1792648942335,"version":"4.5.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,10,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Cardiac fibroblasts (CFs) have the ability to sense stiffness changes and respond to biochemical cues to modulate their states as either quiescent or activated myofibroblasts. Given the potential for secretion of bioactive molecules to modulate the cardiac microenvironment, we sought to determine how the CF secretome changes with matrix stiffness and biochemical cues and how this affects cardiac myocytes via paracrine signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Myofibroblast activation was modulated in vitro by combining stiffness cues with TGF\u03b21 (transforming growth factor \u03b2 1) treatment using engineered poly (ethylene glycol) hydrogels, and in vivo with isoproterenol treatment. Stiffness, TGF\u03b21, and isoproterenol treatment increased AKT (protein kinase B) phosphorylation, indicating that this pathway may be central to myofibroblast activation regardless of the treatment. Although activation of AKT was shared, different activating cues had distinct effects on downstream cytokine secretion, indicating that not all activated myofibroblasts share the same secretome. To test the effect of cytokines present in the CF secretome on paracrine signaling, neonatal rat ventricular cardiomyocytes were treated with CF conditioned media. Conditioned media from myofibroblasts cultured on stiff substrates and activated by TGF\u03b21 caused hypertrophy, and one of the cytokines in that media was insulin growth factor 1, which is a known mediator of cardiac myocyte hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Culturing CFs on stiff substrates, treating with TGF\u03b21, and in vivo treatment with isoproterenol all caused myofibroblast activation. Each cue had distinct effects on the secretome or genes encoding the secretome, but only the secretome of activated myofibroblasts on stiff substrates treated with TGF\u03b21 caused myocyte hypertrophy, most likely through insulin growth factor 1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.120.017025","type":"journal-article","created":{"date-parts":[[2020,9,13]],"date-time":"2020-09-13T05:11:53Z","timestamp":1599973913000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":57,"title":["Defining the Cardiac Fibroblast Secretome in a Fibrotic Microenvironment"],"prefix":"10.1161","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9648-5476","authenticated-orcid":false,"given":"Tova L.","family":"Ceccato","sequence":"first","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology University of Colorado Boulder CO"},{"name":"BioFrontiers Institute University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel B.","family":"Starbuck","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cierra J.","family":"Walker","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute University of Colorado Boulder CO"},{"name":"Materials Science and Engineering Program University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobin E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Applied Chemicals and Materials Division National Institute of Standards and Technology Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Killgore","sequence":"additional","affiliation":[{"name":"Applied Chemicals and Materials Division National Institute of Standards and Technology Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi S.","family":"Anseth","sequence":"additional","affiliation":[{"name":"BioFrontiers Institute University of Colorado Boulder CO"},{"name":"Department of Chemical and Biological Engineering University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-4810","authenticated-orcid":false,"given":"Leslie A.","family":"Leinwand","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology University of Colorado Boulder CO"},{"name":"BioFrontiers Institute University of Colorado Boulder CO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741\u2010020-09940\u20100"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12260"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI40295"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.12.009"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.029622"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.982777"},{"key":"e_1_3_2_8_2","first-page":"1","article-title":"Myofibroblast modulation of cardiac myocyte structure and function","author":"Nagaraju CK","year":"2019","unstructured":"Nagaraju CK, Dries E, Gilbert G, Abdesselem M, Wang N, Amoni M, Driesen RB, Sipido KR. Myofibroblast modulation of cardiac myocyte structure and function. Sci Rep. 2019;1\u201311.","journal-title":"Sci Rep"},{"key":"e_1_3_2_9_2","first-page":"1","article-title":"Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis","author":"Mouton AJ","year":"2019","unstructured":"Mouton AJ, Ma Y, Rivera Gonzalez OJ, Daseke MJ, Flynn ER, Freeman TC, Garrett MR, DeLeon\u2010Pennell KY, Lindsey ML. Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis. Basic Res Cardiol. 2019;1\u201316.","journal-title":"Basic Res Cardiol"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94753"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000020689.12472.E0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00461"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1215"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3032"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.2.770"},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0143802","article-title":"Fn14, a downstream target of the TGF\u2010\u03b2 signaling pathway, regulates fibroblast activation","volume":"9","author":"Chen S","year":"2015","unstructured":"Chen S, Liu J, Yang M, Lai W, Ye L, Chen J, Hou X, Ding H, Zhang W, Wu Y, et al. Fn14, a downstream target of the TGF\u2010\u03b2 signaling pathway, regulates fibroblast activation. PLoS One. 2015;9:e0143802.","journal-title":"PLoS One"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.06.044"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2007.02.002"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1306369110"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01017.2005"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.01.047"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201901989"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e17-01-0014"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8597-5_16"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/28.12.1835"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200704042"},{"key":"e_1_3_2_27_2","first-page":"11","article-title":"Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation","author":"Aguado BA","year":"2019","unstructured":"Aguado BA, Schuetze KB, Grim JC, Walker CJ, Cox AC, Ceccato TL, Tan A, Sucharov CC, Leinwand LA, Taylor MRG, et al. Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation. Sci Transl Med. 2019;11:eaav3233.","journal-title":"Sci Transl Med"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.200901808"},{"key":"e_1_3_2_29_2","first-page":"611","article-title":"Interactions of poly (ethylene) glycols in aqueous solution at 288.0K: ultrasonic studies","author":"Joshi R","year":"2017","unstructured":"Joshi R, Tamta K, Chandra B, Kandpal ND. Interactions of poly (ethylene) glycols in aqueous solution at 288.0K: ultrasonic studies. International Journal of Applied Chemistry. 2017;611\u2010630.","journal-title":"International Journal of Applied Chemistry"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.1143970"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-030-0_18"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt100"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu264"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2013.12.002"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2019.05.011"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-204677"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.120.017025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T07:51:39Z","timestamp":1715586699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.120.017025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,6]]},"references-count":35,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,10,6]]}},"alternative-id":["10.1161\/JAHA.120.017025"],"URL":"https:\/\/doi.org\/10.1161\/jaha.120.017025","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,6]]},"assertion":[{"value":"2020-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e017025"}}