{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T04:58:39Z","timestamp":1767848319181,"version":"3.49.0"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P016278\/1"],"award-info":[{"award-number":["MR\/P016278\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases globally, and this incidence is increasing due to extended lifespans and accumulating comorbidities. Emerging evidence suggests that Wnt signaling plays a role in cardiomyocyte hypertrophy and cardiac fibrosis, which are key features of HFpEF. Furthermore, Porcupine (PORCN) inhibitors, which negatively regulate Wnt signaling, have shown promising results in improving cardiac function and reducing cardiac hypertrophy and\/or fibrosis. This study investigated whether acute oral administration of the PORCN inhibitor, Wnt\u2010c59, alters the maladaptive structural and\/or functional features in a mouse model of HFpEF. Male mice were given a high\u2010fat diet and L\u2010NAME (0.5\u2009g\u2009L<jats:sup>\u22121<\/jats:sup>) in drinking water for 5\u2009weeks, followed by a 2\u2010week intervention of orally administered Wnt\u2010c59 (5\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>\u2009day<jats:sup>\u22121<\/jats:sup>). HFpEF mice were characterized by hypertension, cardiac hypertrophy and fibrosis, and diastolic dysfunction, although there was no evidence of activation of Wnt signaling in the heart. Despite this, short\u2010term treatment of HFpEF mice with Wnt\u2010c59 ameliorated adverse cardiac remodeling by increasing the ratio of the more compliant collagen type 3 to that of the more tensile collagen type 1 in the heart. Furthermore, Wnt\u2010c59 also improved diastolic dysfunction, which was associated with the increased cardiac expression of brain natriuretic peptide, a known promoter of ventricular compliance. Our findings demonstrate that even short\u2010term administration of a PORCN inhibitor improves both the structural and functional features of experimental HFpEF.<\/jats:p>","DOI":"10.1002\/prp2.70054","type":"journal-article","created":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T03:39:58Z","timestamp":1735789198000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Short\u2010Term Oral Administration of the Porcupine Inhibitor, Wnt\u2010c59, Improves the Structural and Functional Features of Experimental <scp>HFpEF<\/scp>"],"prefix":"10.1002","volume":"13","author":[{"given":"Mhairi A.","family":"Paul","sequence":"first","affiliation":[{"name":"School of Pharmacy and Life Sciences, Robert Gordon University  Aberdeen UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1404-965X","authenticated-orcid":false,"given":"Cherry 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