{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:55:53Z","timestamp":1789671353947,"version":"4.0.1"},"reference-count":55,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2020B008"],"award-info":[{"award-number":["2020B008"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Titin\u2010dependent stiffening of cardiomyocytes is a significant contributor to left ventricular (LV) diastolic dysfunction in heart failure with preserved LV ejection fraction (HFpEF). Small heat shock proteins (HSPs), such as HSPB5 and HSPB1, protect titin and administration of HSPB5 in vitro lowers cardiomyocyte stiffness in pressure\u2010overload hypertrophy. In humans, oral treatment with geranylgeranylacetone (GGA) increases myocardial HSP expression, but the functional implications are unknown. Our objective was to investigate whether oral GGA treatment lowers cardiomyocyte stiffness and attenuates LV diastolic dysfunction in a rat model of the cardiometabolic syndrome. Twenty\u2010one\u2010week\u2010old male lean (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200910) and obese (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200920) ZSF1 rats were studied, and obese rats were randomized to receive GGA (200\u2009mg\/kg\/day) or vehicle by oral gavage for 4\u2009weeks. Echocardiography and cardiac catheterization were performed before sacrifice at 25\u2009weeks of age. Titin\u2010based stiffness (F\n                    <jats:sub>passive<\/jats:sub>\n                    ) was determined by force measurements in relaxing solution with 100\u2009nM [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ] in permeabilized cardiomyocytes at sarcomere lengths (SL) ranging from 1.8 to 2.4\u2009\u03bcm. In obese ZSF1 rats, GGA reduced isovolumic relaxation time of the LV without affecting blood pressure, EF or LV weight. In cardiomyocytes, GGA increased myofilament\u2010bound HSPB5 and HSPB1 expression. Vehicle\u2010treated obese rats exhibited higher cardiomyocyte stiffness at all SLs compared to lean rats, while GGA reduced stiffness at SL 2.0\u2009\u03bcm. In obese ZSF1 rats, oral GGA treatment improves cardiomyocyte stiffness by increasing myofilament\u2010bound HSPB1 and HSPB5. GGA could represent a potential novel therapy for the early stage of diastolic dysfunction in the cardiometabolic syndrome.\n                  <\/jats:p>","DOI":"10.14814\/phy2.15788","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T17:34:37Z","timestamp":1700588077000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Geranylgeranylacetone reduces cardiomyocyte stiffness and attenuates diastolic dysfunction in a rat model of cardiometabolic syndrome"],"prefix":"10.14814","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0058-9455","authenticated-orcid":false,"given":"Mark T.","family":"Waddingham","sequence":"first","affiliation":[{"name":"Department of Physiology, Amsterdam Cardiovascular Sciences Amsterdam University Medical Centers  Amsterdam The Netherlands"},{"name":"Department of Cardiac Physiology National Cerebral and Cardiovascular Center  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9192-7674","authenticated-orcid":false,"given":"Vasco","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam Cardiovascular Sciences Amsterdam University Medical Centers  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diederik W. 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