{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T05:01:33Z","timestamp":1791003693450,"version":"4.1.0"},"reference-count":47,"publisher":"The Endocrine Society","issue":"10","funder":[{"name":"AstraZeneca International"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>Mechanisms mediating the cardiovascular and renal protection exerted by SGLT2 inhibitors are still partially unknown. We investigated whether dapagliflozin modulates systemic and renal vascular function and structure, and induces epigenetic modifications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Subjects and Methods<\/jats:title><jats:p>Forty hypertensive patients with type 2 diabetes were randomly assigned to 4-week treatment with dapagliflozin 10 mg or hydrochlorothiazide (HCT) 12.5 mg. Routine analyses; plasma renin activity; aldosterone, catecholamine, and 24-hour urinary electrolyte levels; flow-mediated dilation (FMD) of the brachial artery; carotid-femoral pulse-wave velocity (PWV); augmentation index; and resistive index and dynamic renal resistive index (DRIN) were measured at baseline and after treatment. Circulating miRNAs (miRs) related to heart failure (miR30e-5p, miR199a-3p), endothelial dysfunction (miR27b and miR200b), and renal function (miR130b-3p, miR21-5p) were assessed and related to the effects of treatments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Dapagliflozin and HCT marginally lowered blood pressure. Fasting glucose was lowered, whereas 24-hour diuresis, glycosuria, and osmolar clearance were increased by dapagliflozin (P &lt; 0.001 for all), without affecting sodium excretion and glomerular filtration rate. Magnesium levels significantly increased after dapagliflozin treatment (P = 0.02). Neither dapagliflozin nor HCT modified FMD or PWV. DRIN did not vary in the dapagliflozin group, whereas it increased in the HCT group (P = 0.047 for time by treatment interaction). Both treatments induced variations in the expression of some miRs; dapagliflozin, but not HCT, significantly up-regulated miR30e-5p and downregulated miR199a-3p.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A putative epigenetic regulation of the protecting cardiovascular effect exerted by SGLT2 inhibitors was found. Dapagliflozin might exert nephroprotection by preserving renal vasodilating capacity.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2019-00706","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T13:05:23Z","timestamp":1559653523000},"page":"4253-4263","source":"Crossref","is-referenced-by-count":84,"title":["The Effects of Dapagliflozin on Systemic and Renal Vascular Function Display an Epigenetic Signature"],"prefix":"10.1210","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7855-8253","authenticated-orcid":false,"given":"Anna","family":"Solini","sequence":"first","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Seghieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia","family":"Giannini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Biancalana","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Parolini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Dardano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Taddei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Ghiadoni","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa Maria","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"issue":"2","key":"2019081711250917400_bib1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.2337\/dc17-1096","article-title":"How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial","volume":"41","author":"Inzucchi","year":"2018","journal-title":"Diabetes Care"},{"issue":"5","key":"2019081711250917400_bib2","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1161\/CIRCULATIONAHA.118.034222","article-title":"Canagliflozin and heart failure in type 2 diabetes mellitus: Results From the CANVAS Program","volume":"138","author":"R\u00e5dholm","year":"2018","journal-title":"Circulation"},{"issue":"7","key":"2019081711250917400_bib3","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jdiacomp.2018.04.011","article-title":"Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease","volume":"32","author":"Mima","year":"2018","journal-title":"J Diabetes Complications"},{"issue":"3","key":"2019081711250917400_bib4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1161\/CIRCULATIONAHA.117.029190","article-title":"Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)","volume":"136","author":"Kosiborod","year":"2017","journal-title":"Circulation"},{"issue":"5","key":"2019081711250917400_bib5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S2213-8587(16)00052-8","article-title":"Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis","volume":"4","author":"Wu","year":"2016","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"1","key":"2019081711250917400_bib6","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00592-016-0892-7","article-title":"Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials","volume":"54","author":"Monami","year":"2017","journal-title":"Acta Diabetol"},{"issue":"4","key":"2019081711250917400_bib7","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"},{"issue":"1","key":"2019081711250917400_bib8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s12933-017-0564-0","article-title":"Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study","volume":"16","author":"Shigiyama","year":"2017","journal-title":"Cardiovasc Diabetol"},{"issue":"15","key":"2019081711250917400_bib9","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.2169\/internalmedicine.0701-17","article-title":"The SGLT2 inhibitor dapagliflozin significantly improves the peripheral microvascular endothelial function in patients with uncontrolled type 2 diabetes mellitus","volume":"57","author":"Sugiyama","year":"2018","journal-title":"Intern Med"},{"issue":"1","key":"2019081711250917400_bib10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12933-017-0621-8","article-title":"Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study","volume":"16","author":"Solini","year":"2017","journal-title":"Cardiovasc Diabetol"},{"issue":"Spec No 1","key":"2019081711250917400_bib11","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1093\/hmg\/ddi101","article-title":"Small regulatory RNAs in mammals","volume":"14","author":"Mattick","year":"2005","journal-title":"Hum Mol Genet"},{"issue":"8","key":"2019081711250917400_bib12","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1002\/ejhf.517","article-title":"The transcardiac gradient of cardio-microRNAs in the failing heart","volume":"18","author":"Marques","year":"2016","journal-title":"Eur J Heart Fail"},{"issue":"3","key":"2019081711250917400_bib13","first-page":"4736","article-title":"Plasma levels of microRNA-21, -126 and -423-5p alter during clinical improvement and are associated with the prognosis of acute heart failure","volume":"17","author":"Schneider","year":"2018","journal-title":"Mol Med Rep"},{"key":"2019081711250917400_bib14","doi-asserted-by":"crossref","first-page":"6890501","DOI":"10.1155\/2018\/6890501","article-title":"MicroRNA and microvascular complications of diabetes","volume":"2018","author":"Barutta","year":"2018","journal-title":"Int J Endocrinol"},{"issue":"5","key":"2019081711250917400_bib15","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1097\/FJC.0000000000000419","article-title":"MiR-30s family inhibit the proliferation and apoptosis in human coronary artery endothelial cells through targeting the 3'UTR region of ITGA4 and PLCG1","volume":"68","author":"Ma","year":"2016","journal-title":"J Cardiovasc Pharmacol"},{"issue":"8","key":"2019081711250917400_bib16","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.ejcb.2017.10.001","article-title":"miR-200b downregulates Kruppel Like Factor 2 (KLF2) during acute hypoxia in human endothelial cells","volume":"96","author":"Bartoszewski","year":"2017","journal-title":"Eur J Cell Biol"},{"issue":"1","key":"2019081711250917400_bib17","first-page":"1","article-title":"Circulating microRNA profiles in different arterial territories of stable atherosclerotic disease: a systematic review","volume":"8","author":"Pereira-da-Silva","year":"2018","journal-title":"Am J Cardiovasc Dis"},{"issue":"1","key":"2019081711250917400_bib18","doi-asserted-by":"crossref","first-page":"20475","DOI":"10.1038\/srep20475","article-title":"MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy","volume":"6","author":"Bai","year":"2016","journal-title":"Sci Rep"},{"issue":"1","key":"2019081711250917400_bib19","doi-asserted-by":"crossref","first-page":"12644","DOI":"10.1038\/srep12644","article-title":"Up-regulation of serum MiR-130b-3p level is associated with renal damage in early lupus nephritis","volume":"5","author":"Wang","year":"2015","journal-title":"Sci Rep"},{"issue":"30","key":"2019081711250917400_bib20","doi-asserted-by":"crossref","first-page":"47760","DOI":"10.18632\/oncotarget.10283","article-title":"MicroRNA-27a promotes renal tubulointerstitial fibrosis via suppressing PPAR\u03b3 pathway in diabetic nephropathy","volume":"7","author":"Hou","year":"2016","journal-title":"Oncotarget"},{"issue":"7","key":"2019081711250917400_bib21","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1097\/HJH.0b013e328360f773","article-title":"Renal vasodilating capacity and endothelial function are impaired in patients with obstructive sleep apnea syndrome and no traditional cardiovascular risk factors","volume":"31","author":"Bruno","year":"2013","journal-title":"J Hypertens"},{"issue":"7","key":"2019081711250917400_bib22","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1097\/HJH.0b013e328353f222","article-title":"Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study","volume":"30","author":"Ghiadoni","year":"2012","journal-title":"J Hypertens"},{"issue":"3","key":"2019081711250917400_bib23","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1097\/HJH.0b013e32834fa8b0","article-title":"Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity","volume":"30","author":"Van Bortel","year":"2012","journal-title":"J Hypertens"},{"issue":"9","key":"2019081711250917400_bib24","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/dom.12127","article-title":"Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes","volume":"15","author":"Lambers Heerspink","year":"2013","journal-title":"Diabetes Obes Metab"},{"issue":"1","key":"2019081711250917400_bib25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12933-015-0227-y","article-title":"Predictive value of dynamic renal resistive index (DRIN) for renal outcome in type 2 diabetes and essential hypertension: a prospective study","volume":"14","author":"Bruno","year":"2015","journal-title":"Cardiovasc Diabetol"},{"issue":"2","key":"2019081711250917400_bib26","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/jhg.2016.150","article-title":"Role of miRNAs in the pathogenesis and susceptibility of diabetes mellitus","volume":"62","author":"Hashimoto","year":"2017","journal-title":"J Hum Genet"},{"issue":"12","key":"2019081711250917400_bib27","doi-asserted-by":"crossref","first-page":"E2271","DOI":"10.1210\/jc.2012-1996","article-title":"Circulating miRNA profiles in patients with metabolic syndrome","volume":"97","author":"Karolina","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2019081711250917400_bib28","doi-asserted-by":"crossref","first-page":"216","DOI":"10.2337\/db15-0389","article-title":"Angiogenic microRNAs linked to incidence and progression of diabetic retinopathy in type 1 diabetes","volume":"65","author":"Zampetaki","year":"2016","journal-title":"Diabetes"},{"issue":"9","key":"2019081711250917400_bib29","first-page":"10482","article-title":"Effect of miR-200b on retinal endothelial cell function under high glucose environment","volume":"8","author":"Jiang","year":"2015","journal-title":"Int J Clin Exp Pathol"},{"issue":"8","key":"2019081711250917400_bib30","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1007\/s00392-017-1096-z","article-title":"Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations","volume":"106","author":"Vegter","year":"2017","journal-title":"Clin Res Cardiol"},{"key":"2019081711250917400_bib31","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.ijcard.2015.10.217","article-title":"MicroRNAs relate to early worsening of renal function in patients with acute heart failure","volume":"203","author":"Bruno","year":"2016","journal-title":"Int J Cardiol"},{"key":"2019081711250917400_bib32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.lfs.2016.09.006","article-title":"MiRNA-30e mediated cardioprotection of ACE2 in rats with doxorubicin-induced heart failure through inhibiting cardiomyocytes autophagy","volume":"169","author":"Lai","year":"2017","journal-title":"Life Sci"},{"issue":"2","key":"2019081711250917400_bib33","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1161\/CIRCRESAHA.108.182535","article-title":"miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling","volume":"104","author":"Duisters","year":"2009","journal-title":"Circ Res"},{"issue":"11","key":"2019081711250917400_bib34","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1093\/eurjhf\/hft088","article-title":"Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: responders vs. non-responders","volume":"15","author":"Marfella","year":"2013","journal-title":"Eur J Heart Fail"},{"issue":"3","key":"2019081711250917400_bib35","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.cmet.2013.08.009","article-title":"The hypoxia-inducible microRNA cluster miR-199a\u223c214 targets myocardial PPAR\u03b4 and impairs mitochondrial fatty acid oxidation","volume":"18","author":"el Azzouzi","year":"2013","journal-title":"Cell Metab"},{"issue":"3","key":"2019081711250917400_bib36","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.3892\/or.2016.4916","article-title":"MicroRNA-27a-3p regulates epithelial to mesenchymal transition via targeting YAP1 in oral squamous cell carcinoma cells","volume":"36","author":"Zeng","year":"2016","journal-title":"Oncol Rep"},{"issue":"2","key":"2019081711250917400_bib37","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1159\/000490204","article-title":"MicroRNAs in acute kidney injury","volume":"140","author":"Jones","year":"2018","journal-title":"Nephron"},{"issue":"9","key":"2019081711250917400_bib38","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1007\/s00125-011-2148-y","article-title":"Dynamic evaluation of renal resistive index in normoalbuminuric patients with newly diagnosed hypertension or type 2 diabetes","volume":"54","author":"Bruno","year":"2011","journal-title":"Diabetologia"},{"issue":"1","key":"2019081711250917400_bib39","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.atherosclerosis.2011.05.038","article-title":"Low serum magnesium concentrations predict cardiovascular and all-cause mortality","volume":"219","author":"Reffelmann","year":"2011","journal-title":"Atherosclerosis"},{"issue":"10","key":"2019081711250917400_bib40","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1161\/STROKEAHA.114.005917","article-title":"Plasma magnesium and risk of ischemic stroke among women","volume":"45","author":"Adebamowo","year":"2014","journal-title":"Stroke"},{"issue":"3","key":"2019081711250917400_bib41","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1159\/000341868","article-title":"Relationship between serum magnesium levels and cardiovascular events in chronic kidney disease patients","volume":"36","author":"Kanbay","year":"2012","journal-title":"Am J Nephrol"},{"issue":"8","key":"2019081711250917400_bib42","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1093\/ndt\/gfx275","article-title":"Association of serum magnesium with all-cause mortality in patients with and without chronic kidney disease in the Dallas Heart Study","volume":"33","author":"Ferr\u00e8","year":"2018","journal-title":"Nephrol Dial Transplant"},{"issue":"3","key":"2019081711250917400_bib43","doi-asserted-by":"crossref","first-page":"756","DOI":"10.3945\/ajcn.114.085167","article-title":"Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study","volume":"100","author":"Lutsey","year":"2014","journal-title":"Am J Clin Nutr"},{"issue":"1","key":"2019081711250917400_bib44","doi-asserted-by":"crossref","first-page":"e002707","DOI":"10.1161\/JAHA.115.002707","article-title":"Serum magnesium and the risk of death from coronary heart disease and sudden cardiac death","volume":"5","author":"Kieboom","year":"2016","journal-title":"J Am Heart Assoc"},{"issue":"9","key":"2019081711250917400_bib45","doi-asserted-by":"crossref","first-page":"e0163673","DOI":"10.1371\/journal.pone.0163673","article-title":"Association between density of coronary artery calcification and serum magnesium levels among patients with chronic kidney disease","volume":"11","author":"Sakaguchi","year":"2016","journal-title":"PLoS One"},{"issue":"1","key":"2019081711250917400_bib46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11886-018-0943-5","article-title":"SGLT2 inhibitors and mechanisms of hypertension","volume":"20","author":"Briasoulis","year":"2018","journal-title":"Curr Cardiol Rep"},{"issue":"3","key":"2019081711250917400_bib47","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/jcph.1030","article-title":"Model-based evaluation of proximal sodium reabsorption through SGLT2 in health and diabetes and the effect of inhibition with canagliflozin","volume":"58","author":"Brady","year":"2018","journal-title":"J Clin Pharmacol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/jc.2019-00706\/28760521\/jc.2019-00706.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/104\/10\/4253\/29183707\/jc.2019-00706.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T11:18:39Z","timestamp":1663586319000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/104\/10\/4253\/5510490"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,4]]},"references-count":47,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2019,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2019-00706","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10]]},"published":{"date-parts":[[2019,6,4]]}}}