{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:51:26Z","timestamp":1793641886042,"version":"4.5.1"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Land Baden-W\u00fcrttemberg, Germany","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Medical Faculty of the University of Heidelberg, Germany","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme.","award":["Project no. NVKP_16-1\u20132016-0017 (\u2019National Heart Program\u2019)"],"award-info":[{"award-number":["Project no. NVKP_16-1\u20132016-0017 (\u2019National Heart Program\u2019)"]}]},{"name":"Thematic Excellence Program (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technol-ogy in Hungary, within the framework of the Therapeutic Development and Bioimaging the-matic programs of the Semmelweis University","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"National Research, Development and Innovation Office (NKFIH) of Hungary","award":["K134939"],"award-info":[{"award-number":["K134939"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vascular ischemia\/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9\u201310 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8\u201310 rats) or 50\u00b5M CANA (IR + CANA, n = 9\u201311 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 \u00b1 3.2% vs. IR + CANA 51.9 \u00b1 2.5%, p &lt; 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.<\/jats:p>","DOI":"10.3390\/ijms22157774","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T11:53:23Z","timestamp":1626868403000},"page":"7774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia\/Reperfusion Injury in Rats"],"prefix":"10.3390","volume":"22","author":[{"given":"Sevil","family":"Korkmaz-Ic\u00f6z","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cenk","family":"Kocer","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex A.","family":"Sayour","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Kraft","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona I.","family":"Benker","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Abulizi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2710-2280","authenticated-orcid":false,"given":"Adrian-Iustin","family":"Georgevici","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige","family":"Brlecic","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Radovits","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakkanan","family":"Loganathan","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"Department of Cardiac Surgery, University Hospital Halle (Saale), 06120 Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Karck","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"Department of Cardiac Surgery, University Hospital Halle (Saale), 06120 Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6","article-title":"Pathophysiology of ischaemia-reperfusion injury","volume":"190","author":"Carden","year":"2000","journal-title":"J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1097\/SLA.0b013e318288c38d","article-title":"Saphenous vein graft failure after coronary artery bypass surgery: Pathophysiology, management, and future directions","volume":"257","author":"Harskamp","year":"2013","journal-title":"Ann. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jss.2015.06.062","article-title":"TiProtec preserves endothelial function in a rat model","volume":"200","author":"Veres","year":"2016","journal-title":"J. Surg. Res."},{"key":"ref_4","first-page":"811","article-title":"Even short-time storage in physiological saline solution impairs endothelial vascular function of saphenous vein grafts","volume":"40","author":"Wilbring","year":"2011","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/17425255.2017.1258401","article-title":"Evaluation of the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin for the treatment of type 2 diabetes","volume":"13","author":"Tomlinson","year":"2017","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1002\/jcph.88","article-title":"Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus","volume":"53","author":"Devineni","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12933-019-0869-2","article-title":"The CANVAS Program: Implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus","volume":"18","author":"Carbone","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and renal outcomes in type 2 Diabetes and Nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and cardiovascular and renal events in type 2 Diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jacbts.2018.10.002","article-title":"SGLT2 Inhibitor, Canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart","volume":"4","author":"Lim","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00125-020-05359-2","article-title":"Sodium-glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia-reperfusion injury: A meta-analysis","volume":"64","author":"Sayour","year":"2021","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12967-019-1881-8","article-title":"Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation","volume":"17","author":"Sayour","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Uthman, L., Kuschma, M., Romer, G., Boomsma, M., Kessler, J., Hermanides, J., Hollmann, M.W., Preckel, B., Zuurbier, C.J., and Weber, N.C. (2020). Novel anti-inflammatory effects of Canagliflozin involving Hexokinase II in Lipopolysaccharide-stimulated human coronary artery Endothelial cells. Cardiovasc. Drugs Ther.","DOI":"10.1007\/s10557-020-07083-w"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5276","DOI":"10.1038\/s41598-018-23420-4","article-title":"Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms","volume":"8","author":"Mancini","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.5551\/jat.52100","article-title":"Canagliflozin prevents diabetes-induced vascular dysfunction in ApoE-deficient mice","volume":"27","author":"Rahadian","year":"2020","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1046\/j.1538-7836.2003.00292.x","article-title":"The role of inflammation in vascular injury and repair","volume":"1","author":"Davis","year":"2003","journal-title":"J. Thromb. Haemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1111\/jcmm.14233","article-title":"Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence","volume":"24","author":"Belcastro","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11906-003-0055-4","article-title":"Endothelial nitric oxide synthase and endothelial dysfunction","volume":"5","author":"Huang","year":"2003","journal-title":"Curr. Hypertens Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1161\/01.ATV.0000170136.71970.5f","article-title":"PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress","volume":"25","author":"Bagi","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1172\/JCI119129","article-title":"The biology of PECAM-1","volume":"99","author":"Newman","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/ki.1990.221","article-title":"Differing regulation and function of ICAM-1 and class II antigens on renal tubular cells","volume":"38","author":"Jevnikar","year":"1990","journal-title":"Kidney Int."},{"key":"ref_24","first-page":"1425","article-title":"Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues","volume":"54","author":"Koong","year":"1994","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/sj.jid.5700670","article-title":"Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations","volume":"127","author":"Clark","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.vph.2018.06.006","article-title":"Hyperglycaemic impairment of PAR2-mediated vasodilation: Prevention by inhibition of aortic endothelial sodium-glucose-co-Transporter-2 and minimizing oxidative stress","volume":"109","author":"Saifeddine","year":"2018","journal-title":"Vascul. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s11255-020-02481-3","article-title":"A unifying model of glucotoxicity in human renal proximal tubular epithelial cells and the effect of the SGLT2 inhibitor dapagliflozin","volume":"52","author":"Eleftheriadis","year":"2020","journal-title":"Int. Urol. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6791","DOI":"10.1038\/s41598-018-25054-y","article-title":"High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in renal tubules through Glucose Transporter-2 Detection","volume":"8","author":"Umino","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"F1100","DOI":"10.1152\/ajprenal.00607.2019","article-title":"Gene knockout of the Na(+)-glucose cotransporter SGLT2 in a murine model of acute kidney injury induced by ischemia-reperfusion","volume":"318","author":"Nespoux","year":"2020","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"F1201","DOI":"10.1152\/ajprenal.00111.2019","article-title":"Gene deletion of the Na(+)-glucose cotransporter SGLT1 ameliorates kidney recovery in a murine model of acute kidney injury induced by ischemia-reperfusion","volume":"316","author":"Nespoux","year":"2019","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1093\/cvr\/cvz037","article-title":"Cardiac sodium-dependent glucose cotransporter 1 is a novel mediator of ischaemia\/reperfusion injury","volume":"115","author":"Li","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13700","DOI":"10.1038\/s41598-021-93156-1","article-title":"Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial alpha1AMPK","volume":"11","author":"Ange","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1161\/CIRCULATIONAHA.109.862771","article-title":"Soluble CD40 ligand impairs the function of peripheral blood angiogenic outgrowth cells and increases neointimal formation after arterial injury","volume":"121","author":"Hristov","year":"2010","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.freeradbiomed.2010.04.030","article-title":"NADPH oxidases in cardiovascular disease","volume":"49","author":"Brandes","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1124\/jpet.112.200790","article-title":"Prolyl-hydroxylase inhibition preserves endothelial cell function in a rat model of vascular ischemia reperfusion injury","volume":"345","author":"Barnucz","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.healun.2007.11.002","article-title":"Endothelial dysfunction after long-term cold storage in HTK organ preservation solutions: Effects of iron chelators and N-alpha-acetyl-L-histidine","volume":"27","author":"Radovits","year":"2008","journal-title":"J. Heart Lung Transplant."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.ejvs.2013.05.006","article-title":"Addition of vardenafil into storage solution protects the endothelium in a hypoxia-reoxygenation model","volume":"46","author":"Veres","year":"2013","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1177\/1074248412455696","article-title":"Nitric oxide- and heme-independent activation of soluble guanylate cyclase attenuates peroxynitrite-induced endothelial dysfunction in rat aorta","volume":"18","author":"Korkmaz","year":"2013","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/ejcts\/ezw426","article-title":"Prolonging hypothermic ischaemic cardiac and vascular storage by inhibiting the activation of the nuclear enzyme poly (adenosine diphosphate-ribose) polymerase","volume":"51","author":"Radovits","year":"2017","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.jdiacomp.2015.06.012","article-title":"Mild type 2 diabetes mellitus improves remote endothelial dysfunction after acute myocardial infarction","volume":"29","author":"Vater","year":"2015","journal-title":"J. Diabetes Complicat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.healun.2018.12.003","article-title":"Hypothermic perfusion of donor heart with a preservation solution supplemented by mesenchymal stem cells","volume":"38","author":"Li","year":"2019","journal-title":"J. Heart Lung Transplant."},{"key":"ref_42","first-page":"884","article-title":"Impairment of the Akt pathway in transplanted Type 1 diabetic hearts is associated with post-transplant graft injury","volume":"27","author":"Li","year":"2018","journal-title":"Interact. Cardiovasc. Thorac. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13","DOI":"10.18637\/jss.v036.i11","article-title":"Feature Selection with the Boruta Package","volume":"36","author":"Kursa","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gansner, E.R., Koren, Y., and North, S. (2004). Graph drawing by stress majorization. International Symposium on Graph Drawing, Springer.","DOI":"10.1007\/978-3-540-31843-9_25"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/7774\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:32:40Z","timestamp":1760164360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/7774"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":44,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22157774"],"URL":"https:\/\/doi.org\/10.3390\/ijms22157774","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]}}}