{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:09:08Z","timestamp":1747188548594,"version":"3.40.5"},"reference-count":34,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T00:00:00Z","timestamp":1684108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/17\/10\/32859","FS\/17\/58\/33072","CH\/16\/1\/32013"],"award-info":[{"award-number":["RG\/17\/10\/32859","FS\/17\/58\/33072","CH\/16\/1\/32013"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["090532\/Z\/09\/Z"],"award-info":[{"award-number":["090532\/Z\/09\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthases in which its production of NO is crucial for cardiac function. However, non\u2010canonical roles of BH4 have been discovered recently and the cell\u2010specific role of cardiomyocyte BH4 in cardiac function and metabolism remains to be elucidated. Therefore, we developed a novel mouse model of cardiomyocyte BH4 deficiency, by cardiomyocyte\u2010specific deletion of <jats:italic>Gch1<\/jats:italic>, which encodes guanosine triphosphate cyclohydrolase I, a required enzyme for <jats:italic>de novo<\/jats:italic> BH4 synthesis. Cardiomyocyte (cm)<jats:italic>Gch1<\/jats:italic> mRNA expression and BH4 levels from cm<jats:italic>Gch1<\/jats:italic> KO mice were significantly reduced compared to <jats:italic>Gch1<jats:sup>flox\/flox<\/jats:sup><\/jats:italic> (WT) littermates. Transcriptomic analyses and protein assays revealed downregulation of genes involved in fatty acid oxidation in cm<jats:italic>Gch1<\/jats:italic> KO hearts compared with WT, accompanied by increased triacylglycerol concentration within the myocardium. Deletion of cardiomyocyte BH4 did not alter basal cardiac function. However, the recovery of left ventricle function was improved in cm<jats:italic>Gch1<\/jats:italic> KO hearts when subjected to <jats:italic>ex vivo<\/jats:italic> ischaemia\u2013reperfusion (IR) injury, with reduced infarct size compared to WT hearts. Metabolomic analyses of cardiac tissue after IR revealed that long\u2010chain fatty acids were increased in cm<jats:italic>Gch1<\/jats:italic> KO hearts compared to WT, whereas at 5\u00a0min reperfusion (post\u201035\u00a0min ischaemia) fatty acid metabolite levels were higher in WT compared to cm<jats:italic>Gch1<\/jats:italic> KO hearts. These results indicate a new role for BH4 in cardiomyocyte fatty acid metabolism, such that reduction of cardiomyocyte BH4 confers a protective effect in response to cardiac IR injury. Manipulating cardiac metabolism via BH4 could play a therapeutic role in limiting IR injury.<\/jats:p>","DOI":"10.1113\/ep090795","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T13:56:26Z","timestamp":1684158986000},"page":"874-890","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiomyocyte tetrahydrobiopterin synthesis regulates fatty acid metabolism and susceptibility to ischaemia\u2013reperfusion injury"],"prefix":"10.1113","volume":"108","author":[{"given":"Sandy M.","family":"Chu","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa C.","family":"Heather","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics 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