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Upregulation of Na<jats:sup>+<\/jats:sup>\/H<jats:sup>+<\/jats:sup> exchanger 1 (NHE1), SGLT1, and Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> homeostasis via ERK and eNOS signaling. AMI (+) and AMI (\u2212) serum levels were estimated using ELISA assays of TGF\u03b2\u20101 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1\u2009Hz for 24\u2009h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1\/2, eNOS<jats:sup>S633<\/jats:sup>, and ERK1\/2<jats:sup>T202\/Y204<\/jats:sup> levels was performed for 5% (mild), and 25% elongation for 24\u2009h. AMI (+) serum showed increased TGF\u03b21 and CD105 compared to AMI (\u2212) patients. In consistent, troponin I, CD105, SGLT1\/2, eNOS<jats:sup>S633<\/jats:sup> and ERK1\/2<jats:sup>T202\/Y204<\/jats:sup> were upregulated after 25% of 24\u2009h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1\/2, eNOS<jats:sup>S633<\/jats:sup>, and ERK1\/2<jats:sup>T202\/Y204<\/jats:sup> under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in\u00a0vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P\u2010ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in\u00a0vitro cardiac overloaded cell model, an alternative to animal heart model.<\/jats:p>","DOI":"10.14814\/phy2.15990","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T02:59:05Z","timestamp":1712285945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dapagliflozin prevents ERK activation and SGLT2\u2010dependent endoglin upregulation in a mechanically provoked cardiac injury model"],"prefix":"10.14814","volume":"12","author":[{"given":"Tung\u2010Chen","family":"Yeh","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Kaohsiung Veterans General Hospital  Kaohsiung Taiwan"},{"name":"Institute of Biomedical Sciences 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