{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:45:05Z","timestamp":1785548705503,"version":"3.56.0"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Programme of China","doi-asserted-by":"publisher","award":["2023YFA1801200"],"award-info":[{"award-number":["2023YFA1801200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["T2288101"],"award-info":[{"award-number":["T2288101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82130010"],"award-info":[{"award-number":["82130010"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82500458"],"award-info":[{"award-number":["82500458"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Basic research projects of Shanghai Science and Technology Commission","award":["22JC1400500"],"award-info":[{"award-number":["22JC1400500"]}]},{"name":"the Shanghai Top Priority research center construction project","award":["2022ZZ01010"],"award-info":[{"award-number":["2022ZZ01010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Histamine signalling is critical in heart failure (HF). Histamine N-methyltransferase (HNMT) serves as the primary enzyme responsible for histamine clearance in heart, but its role in HF remains undefined. This study investigates HNMT-mediated metabolic-epigenetic crosstalk in HF and evaluates therapeutic strategies targeting this axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cardiomyocyte-specific Hnmt-knockout and Hnmt-overexpression mice were generated. Transverse aortic constriction (TAC) was applied to induce HF in mice. RNA sequencing and targeted metabolomics were employed to explore mechanisms underlying the pathological role of HNMT. Urinary N-methylhistamine levels were measured in a cohort of 53 HF and 55 control individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HNMT was up-regulated in cardiac tissues from HF patients, TAC-operated mice, and phenylephrine (PE)-treated neonatal mouse cardiomyocytes (NMCMs). Urinary N-methylhistamine levels were elevated in HF patients and positively correlated with severity of HF. In mice, cardiomyocyte-specific Hnmt deletion mitigated hypertrophy and HF induced by TAC or angiotensin II. Pharmacological HNMT inhibition with amodiaquine ameliorated TAC-induced cardiac dysfunction. Conversely, Hnmt overexpression impaired cardiac function. Mechanistically, HNMT reduced intracellular S-adenosylmethionine (SAM) and impaired enhancer of zeste homologue 2 (EZH2) function, decreasing histone 3 lysine 27 trimethylation (H3K27me3) modification at the frizzled-2 (Fzd2) promoter. FZD2 up-regulation activated the WNT\/calcium\/calmodulin-dependent protein kinase II (CaMKII) pathway, promoting HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HNMT exacerbates pathological hypertrophy and HF through SAM\/FZD2\/CaMKII axis. Amodiaquine, the inhibitor of HNMT, shows therapeutic potential against HF. Urinary N-methylhistamine emerges as a non-invasive HF biomarker.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehaf1065","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T13:02:44Z","timestamp":1765630964000},"page":"2345-2363","source":"Crossref","is-referenced-by-count":6,"title":["Histamine N-methyltransferase upregulation, cardiac hypertrophy, and heart failure"],"prefix":"10.1093","volume":"47","author":[{"given":"Jinyan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases , No. 1609 Xietu Road, District Xuhui, Shanghai ,","place":["China"]},{"name":"State Key Laboratory of Cardiology, Zhongshan Hospital, Fudan University , Shanghai ,","place":["China"]},{"name":"NHC Key Laboratory of Ischemic Heart Diseases , Shanghai ,","place":["China"]},{"name":"Key Laboratory of Viral Heart Diseases, Chinese 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