The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following <i>In Vitro</i> Vascular Ischemia/Reperfusion Injury in Rats

• Main Authors: Sevil Korkmaz-Icöz, Cenk Kocer, Alex A. Sayour, Patricia Kraft, Mona I. Benker, Sophia Abulizi, Adrian-Iustin Georgevici, Paige Brlecic, Tamás Radovits, Sivakkanan Loganathan, Matthias Karck, Gábor Szabó
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: ischemia/reperfusion; endothelial function; canagliflozin; sodium-glucose cotransporter-2; diabetes mellitus
• Online Access: https://www.mdpi.com/1422-0067/22/15/7774

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 = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 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 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, <i>p</i> < 0.05). IR altered the expression of 17 genes. <i>Ccl2</i>, <i>Ccl3</i>, <i>Ccl4</i>, <i>CxCr4</i>, <i>Fos</i>, <i>Icam1</i>, <i>Il10</i>, <i>Il1a</i> and <i>Il1b</i> have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of <i>Il1a</i> and <i>Il6</i>, 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.