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However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1\/3\/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.<\/jats:p>","DOI":"10.3390\/ijms25158541","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T18:21:40Z","timestamp":1722882100000},"page":"8541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Beneficial Effect of the SGLT2 Inhibitor Dapagliflozin in Alleviating Acute Myocardial Infarction-Induced Cardiomyocyte Injury by Increasing the Sirtuin Family SIRT1\/SIRT3 and Cascade Signaling"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-9037","authenticated-orcid":false,"given":"Yi-Hsiung","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Center for Lipid Biosciences, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1123-6954","authenticated-orcid":false,"given":"Wei-Chung","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Department of Internal Medicine, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-2468","authenticated-orcid":false,"given":"Chien-Chih","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"The Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Yu","family":"Chi","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6915-3679","authenticated-orcid":false,"given":"Yi-Hsueh","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tien-Chi","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Tsung","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7226-8730","authenticated-orcid":false,"given":"Tsung-Hsien","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Ter","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Hsiung","family":"Sheu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6217-3036","authenticated-orcid":false,"given":"Po-Chao","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Center for Lipid Biosciences, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan"},{"name":"Department of Internal Medicine, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung 80756, 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(2022). SGLT2 Inhibitors: The Statins of the 21st Century, Oxford University Press.","DOI":"10.1093\/eurheartj\/ehab765"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/00325481.2018.1423852","article-title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","volume":"130","author":"Guthrie","year":"2018","journal-title":"Postgrad. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in patients with heart failure and reduced ejection fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/j.jacc.2021.07.046","article-title":"Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-reduced trial","volume":"78","author":"Januzzi","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s00125-017-4509-7","article-title":"Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: Inhibition of Na(+)\/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation","volume":"61","author":"Uthman","year":"2018","journal-title":"Diabetologia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1161\/CIRCULATIONAHA.122.060805","article-title":"SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism","volume":"146","author":"Mayr","year":"2022","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/s44161-023-00352-5","article-title":"Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure","volume":"2","author":"Angermann","year":"2023","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1620\/tjem.210.247","article-title":"Persistent oxidative stress after myocardial infarction treated by percutaneous coronary intervention","volume":"210","author":"Rabuzin","year":"2006","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Collet, J.-P., and Thiele, H. (2020). The \u2018Ten Commandments\u2019 for the 2020 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation, Oxford University Press.","DOI":"10.1093\/eurheartj\/ehaa624"},{"key":"ref_12","first-page":"285","article-title":"2020 focused update of the 2012 guidelines of the Taiwan Society of Cardiology for the management of ST-segment elevation myocardial infarction","volume":"36","author":"Li","year":"2020","journal-title":"Acta Cardiol. Sin."},{"key":"ref_13","first-page":"1089","article-title":"DELIVER Trial Committees and Investigators","volume":"387","author":"Solomon","year":"2022","journal-title":"Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in heart failure with a preserved ejection fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102417","DOI":"10.1016\/j.dsx.2022.102417","article-title":"Empagliflozin improves quality of life in nondiabetic HFrEF patients. Sub-analysis of the EMPATROPISM trial","volume":"16","year":"2022","journal-title":"Diabetes Metab. Syndr."},{"key":"ref_16","first-page":"e015298","article-title":"Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction","volume":"16","author":"Picatoste","year":"2023","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s12933-022-01506-8","article-title":"Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: A multicenter international registry","volume":"21","author":"Paolisso","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.1093\/eurheartj\/ehac494","article-title":"Empagliflozin in acute myocardial infarction: The EMMY trial","volume":"43","author":"Kolesnik","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_19","first-page":"EVIDoa2300286","article-title":"Dapagliflozin in myocardial infarction without diabetes or heart failure","volume":"3","author":"James","year":"2023","journal-title":"NEJM Evid."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1016\/j.jacc.2022.03.353","article-title":"Sodium glucose cotransporter-2 inhibition for acute myocardial infarction: JACC review topic of the week","volume":"79","author":"Udell","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1056\/NEJMoa2314051","article-title":"Empagliflozin after Acute Myocardial Infarction","volume":"390","author":"Butler","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.18632\/oncotarget.12157","article-title":"Sirtuins in glucose and lipid metabolism","volume":"8","author":"Ye","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.semcancer.2018.11.003","article-title":"The roles of sirtuins family in cell metabolism during tumor development","volume":"57","author":"Zhu","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1186\/s13046-016-0461-5","article-title":"Sirtuins in metabolism, DNA repair and cancer","volume":"35","author":"Mei","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/onc.2013.120","article-title":"Sorting out functions of sirtuins in cancer","volume":"33","author":"Roth","year":"2014","journal-title":"Oncogene"},{"key":"ref_26","first-page":"33","article-title":"Serum sirtuin 1, 3 and 6 levels in acute myocardial infarction patients","volume":"113","author":"Kundi","year":"2019","journal-title":"Arq. Bras. De Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1089\/ars.2017.7178","article-title":"SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection","volume":"28","author":"Servillo","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e24586","DOI":"10.1002\/jcla.24586","article-title":"SIRT3 attenuates coronary atherosclerosis in diabetic patients by regulating endothelial cell function","volume":"36","author":"Gong","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2284366","DOI":"10.1080\/07853890.2023.2284366","article-title":"Elevated circulating inflammatory biomarker levels in the SIRT1-NF-\u03baB-sCD40L pathway in patients with acute myocardial infarction: A case-control study","volume":"55","author":"Chen","year":"2023","journal-title":"Ann. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100965","DOI":"10.1016\/j.mgene.2021.100965","article-title":"Sirtuin1 and Sirtuin3 gene polymorphisms and acute myocardial infarction susceptibility","volume":"30","year":"2021","journal-title":"Meta Gene"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Marshall, G.M., Liu, P.Y., Gherardi, S., Scarlett, C.J., Bedalov, A., Xu, N., Iraci, N., Valli, E., Ling, D., and Thomas, W. (2011). SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002135"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1101\/gad.350736.123","article-title":"MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival","volume":"37","author":"Hurd","year":"2023","journal-title":"Genes Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8541\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:30:23Z","timestamp":1760110223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/15\/8541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,5]]},"references-count":32,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25158541"],"URL":"https:\/\/doi.org\/10.3390\/ijms25158541","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,5]]}}}