{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:56:32Z","timestamp":1792799792697,"version":"4.5.0"},"reference-count":44,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":90,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JST FOREST Program","award":["JPMJFR200L"],"award-info":[{"award-number":["JPMJFR200L"]}]},{"name":"JSPS","award":["23K27602"],"award-info":[{"award-number":["23K27602"]}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP21gm5010002"],"award-info":[{"award-number":["JP21gm5010002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JSPS","award":["16H06244"],"award-info":[{"award-number":["16H06244"]}]},{"name":"JSPS","award":["22K08215"],"award-info":[{"award-number":["22K08215"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that develops in several clinical settings. Despite its complex pathogenesis, evidence indicates a central role for fibrosis in the progression of left ventricular diastolic dysfunction (LVDD). Through exploratory research into adipokines derived from brown adipose tissue (BAT), we identified a secreted-type profibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), whose expression increased in BAT with aging. PCPE-1 promotes the cleavage of procollagens and is a critical initiator of fibrillogenesis. This molecule was increased in the plasma of aged mice. In addition to aging, obesity led to an increase in PCPE-1 expression in the LV of mice. Both systemic and BAT-specific PCPE-1 depletion ameliorated LV fibrosis and LVDD in the obese HFpEF model. Our data also showed that age-associated LVDD was ameliorated in the systemic PCPE-1\u2013KO mouse fed with a normal chow diet. Conversely, the overexpression of PCPE-1 expression in BAT was shown to lead to aggravation of LV fibrosis and LVDD. Mechanistically, we found ROS\/DNA damage\/c-Fos\/c-Jun signaling resulted in an increased production of PCPE-1 in brown adipocytes. These results indicate PCPE-1 may represent a druggable target for aging- and obesity-related HFpEF.<\/jats:p>","DOI":"10.1172\/jci.insight.195508","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T16:00:15Z","timestamp":1775750415000},"source":"Crossref","is-referenced-by-count":5,"title":["PCPE-1 promotes cardiac fibrosis with aging and obesity"],"prefix":"10.1172","volume":"11","author":[{"given":"Yung-Ting","family":"Hsiao","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohko","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"},{"name":"Department of Advanced Senotherapeutics, Juntendo University Graduate School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-2520","authenticated-orcid":true,"given":"Hirotsugu","family":"Tsuchimochi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin May","family":"Aung","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Han","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agian Jeffilano","family":"Barinda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."},{"name":"Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur Syakirah Binti","family":"Othman","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Yoshizaki","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Ling","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7704-8104","authenticated-orcid":true,"given":"Shujiro","family":"Okuda","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8534-2138","authenticated-orcid":true,"given":"Manabu","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Cellular Neurobiology, Brain Research Institute, and"},{"name":"Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiya","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Ibaraki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8540-7760","authenticated-orcid":true,"given":"Satoru","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Ibaraki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Inomata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Kioka","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sakata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Osaka Graduate School of Medicine, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Matsue","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Furihata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3318-5406","authenticated-orcid":true,"given":"James T.","family":"Pearson","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinya","family":"Otsu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Pathophysiology and Therapeutics, The University of Osaka Graduate School of Medicine, Osaka, Japan."},{"name":"National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-2276","authenticated-orcid":true,"given":"Kenneth","family":"Walsh","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Ishigami","sequence":"additional","affiliation":[{"name":"Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Minamino","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ippei","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Aging, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan."},{"name":"Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvac013"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32279-7"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.08.074"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911303"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1409077"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915928"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61198-1"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2206286"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107038"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2410027"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00469-0"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01643-X"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-043024-011141"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2023.01.049"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.2020"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.09.006"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000124490.27666.B2"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-024-00196-0"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101629"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.mbplus.2021.100062"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nri2921"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.12.012"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.09.001"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1126\/science.7678183"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03043-1"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.038010"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60433"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714431115"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705287114"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810780"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2021.12.009"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchf.2020.04.007"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81870"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-19245-x"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature24045"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2228-6"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa1012"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2007.01.004"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2018.06.019"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2020.04.007"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.49.34795"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.1.319-329.2001"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/195508\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T18:01:48Z","timestamp":1783447308000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/195508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":44,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7,8]]},"published-print":{"date-parts":[[2026,7,8]]}},"alternative-id":["10.1172\/jci.insight.195508"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.195508","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"article-number":"e195508"}}