{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:39:09Z","timestamp":1791567549366,"version":"4.3.4"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["17K09741"],"award-info":[{"award-number":["17K09741"]}]},{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["24590336"],"award-info":[{"award-number":["24590336"]}]},{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["21590295"],"award-info":[{"award-number":["21590295"]}]},{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["15590240"],"award-info":[{"award-number":["15590240"]}]},{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["13670102"],"award-info":[{"award-number":["13670102"]}]},{"name":"Ministry of Education, Science, Sports, and Culture in Japan","award":["20K08601"],"award-info":[{"award-number":["20K08601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In addition to its role in angiotensin II (Ang II) production, chymase exhibits various functions, including activation of latent transforming growth factor beta 1 (TGF-\u03b21) and pro-matrix metalloproteinases (MMPs). However, the extent to which these Ang II-independent functions contribute to pathological conditions remains unclear. In this study, we investigated the Ang II-independent roles of chymase in cardiac remodeling and dysfunction. Eighteen male Syrian hamsters, aged 6 weeks and weighing 90\u2013110 g, were used. Exogenous Ang II was administered to a hamster model that mirrors the human chymase-dependent Ang II production pathway, via subcutaneous osmotic mini pumps (2 mg\/kg\/day) for 4 weeks. A chymase-specific inhibitor, TY-51469 (10 mg\/kg\/day), was given daily starting 1 day after commencement of Ang II infusion. Evaluation showed that while systolic blood pressure increased significantly, only diastolic dysfunction developed over time. Ang II treatment led to elevated cardiac expression of chymase, TGF-\u03b21, and MMP-2, and increased the number of chymase-positive mast cells, resulting in notable cardiac hypertrophy and fibrosis. TY-51469 effectively suppressed these molecular changes and improved both cardiac structure and diastolic dysfunction, despite continued Ang II exposure. These results suggest that chymase promotes cardiac remodeling and dysfunction not only through Ang II generation but also by activating profibrotic and matrix-degrading factors, such as TGF-\u03b21 and MMP-2.<\/jats:p>","DOI":"10.3390\/ijms26178236","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:26:31Z","timestamp":1756189591000},"page":"8236","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Beneficial Effects of Chymase Inhibition on Cardiac Diastolic Function and Remodeling Induced by Chronic Angiotensin II Stimulation"],"prefix":"10.3390","volume":"26","author":[{"given":"Shiguma","family":"Taniguchi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5820-8168","authenticated-orcid":false,"given":"Denan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"},{"name":"Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0985-0161","authenticated-orcid":false,"given":"Hirofumi","family":"Morihara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0069-8447","authenticated-orcid":false,"given":"Shunichi","family":"Yokoe","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8557-7826","authenticated-orcid":false,"given":"Kazumasa","family":"Moriwaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-4477","authenticated-orcid":false,"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"},{"name":"Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City 569-8686, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1161\/01.CIR.98.21.2334","article-title":"Sudden cardiac death","volume":"98","author":"Zipes","year":"1998","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1161\/HHF.0b013e318291329a","article-title":"Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association","volume":"6","author":"Heidenreich","year":"2013","journal-title":"Circ. 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