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Whether sodium\u2010glucose cotransporter\u20102 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte\u2010specific\n                    <jats:italic>Dsg2<\/jats:italic>\n                    exon\u201011 knockout and wild\u2010type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1\u00a0mg\/kg\/day) or vehicle alone for 8\u2009weeks. HL\u20101 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM\u2010associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF\u20102\u03b1 and HIF\u20101\u03b1 were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF\u2010\u03baB P65 and I\u03baB phosphorylation, as well as fibrosis indicators (including TGF\u2010\u03b2, \u03b1\u2010SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the I\u03baB phosphorylation and NF\u2010\u03baB p65 transcriptional activity in\n                    <jats:italic>DSG2<\/jats:italic>\n                    \u2010knockdown HL\u20101 cells. Interestingly, the elective HIF\u20102\u03b1 inhibitor PT2399 almost completely blunted the DAPA\u2010mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM\u2010associated cardiac dysfunction and adverse remodeling in a glucose\u2010independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF\u20102\u03b1 signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200243r","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T11:43:27Z","timestamp":1655466207000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["<scp>SGLT2<\/scp>\n                    inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the\n                    <scp>HIF<\/scp>\n                    \u20102\u03b1 signaling pathway in arrhythmogenic cardiomyopathy"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1925-2801","authenticated-orcid":false,"given":"Zhe","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Zhuhai Hospital Affiliated with Jinan University (Zhuhai People's Hospital) Jinan University  Zhuhai China"},{"name":"The First Dongguan Affiliated Hospital Guangdong Medical University  Dongguan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengling","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Xian","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Biomedical Imaging 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