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Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin\u2014SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Cardiomyopathy was induced in diabetic mice (db\/db) by subcutaneous infusion of angiotensin II (ATII) for 30\u00a0days using an osmotic pump. Dapagliflozin (1.5\u00a0mg\/kg\/day) was administered concomitantly in drinking water. Male homozygous, 12\u201314\u00a0weeks old WT or db\/db mice (n\u2009=\u20094\u20138\/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5\u201333\u00a0mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Angiotensin II infusion induced cardiomyopathy in db\/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNF\u03b1, TLR4). Dapagliflozin decreased blood glucose (874\u2009\u00b1\u2009111 to 556\u2009\u00b1\u200957\u00a0mg\/dl, p\u2009&lt;\u20090.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db\/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium\u2013calcium exchanger (NCX) and the sodium\u2013hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and\u00a0improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12933-019-0980-4","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T09:03:34Z","timestamp":1578647014000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":196,"title":["Sodium\u2013glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy"],"prefix":"10.1186","volume":"19","author":[{"given":"M.","family":"Arow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Waldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Yadin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Nudelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Shainberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. 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