{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:30:38Z","timestamp":1789032638747,"version":"build-2803163510"},"reference-count":39,"publisher":"Portland Press Ltd.","issue":"17","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,9,10]]},"abstract":"<jats:p>Heart failure with preserved ejection fraction (HFpEF) represents the initial phase of cardiac dysfunction associated with type 2 diabetes mellitus (T2DM). To date, the pathophysiological mechanisms underlying T2DM-induced HFpEF are complex and elusive. Fibroblast activation protein (FAP) is a prolyl-specific serine protease whose inhibition or vaccination has been shown to enhance cardiac repair following myocardial infarction (MI). However, the role and underlying molecular mechanisms by which abnormal FAP activity promotes the development of T2DM-induced HFpEF remain to be elucidated. In this study, the plasma activity and level of FAP were significantly higher in the T2DM with HFpEF group compared with the healthy control group. Moreover, plasma FAP activity and level were positively correlated with the likelihood of T2DM with HFpEF. To investigate the mechanistic involvement of FAP in the development of T2DM-associated HFpEF, a chronic T2DM mouse model was established. The results revealed that FAP knockout (KO) significantly improved B-type natriuretic peptide (BNP) level and E\/A ratios compared with the wildtype (WT) T2DM group. Additionally, FAP KO and FAP inhibitor Talabostat alleviated myocardial inflammation, fibrosis, cardiomyocyte apoptosis, oxidative stress, and energy metabolism dysfunction. Mechanistically, an abnormal increase in FAP triggered the calmodulin-dependent protein kinase \u03b4 (CaMKII\u03b4)-Calcineurin A-NFATc2 signaling pathway, leading to the aforementioned pathological changes in T2DM-induced HFpEF. In contrast, FAP KO suppressed the CaMKII\u03b4-Calcineurin A-NFATc2 signaling pathway and attenuated these pathological changes. Overall, these findings suggest that FAP may serve as a critical therapeutic target for T2DM-induced HFpEF.<\/jats:p>","DOI":"10.1042\/cs20256808","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T08:29:58Z","timestamp":1756196998000},"page":"923-940","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["FAP deficiency attenuates T2DM-associated HFpEF by suppressing the CaMKII\u03b4-Calcineurin A-NFATc2 signaling pathway"],"prefix":"10.1042","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4565-7164","authenticated-orcid":false,"given":"Chao","family":"Li","sequence":"first","affiliation":[{"name":"1Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-3191","authenticated-orcid":false,"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"2Institute of Cardio-Cerebrovascular Medicine, Central Hospital of Dalian University of Technology, Dalian, 116089, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0078-4199","authenticated-orcid":false,"given":"Jia-Kang","family":"He","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8113-3383","authenticated-orcid":false,"given":"Sheng-Xing","family":"Tang","sequence":"additional","affiliation":[{"name":"3Department of Cardiology, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4239-1786","authenticated-orcid":false,"given":"Yun-Long","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Department of Cardiology, Yijishan Hospital of Wannan Medical College, Wuhu, 241000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0200-6591","authenticated-orcid":false,"given":"Xiao-Hong","family":"Yu","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3512-1157","authenticated-orcid":false,"given":"Lian-Jun","family":"Gao","sequence":"additional","affiliation":[{"name":"1Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"2026062905470319700_CS-2025-6808C1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat. 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