The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction of Vascular Grafts Submitted to In-Vitro Ischemia/Reperfusion Injury in Nondiabetic Rats

Objectives: Ischemia/reperfusion (IR) injury is a challenge during coronary artery bypass surgery. It can induce vascular graft injury. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, used for treating patients with type 2 diabetes, have been shown to protect against myocardial IR injury in experimental models, irrespective of diabetes. We hypothesized that physiological saline-supplemented canagliflozin (CANA), a SGLT2 inhibitor, protects vascular grafts from IR injury in rats.

Methods: Thoracic aortic rings from non-diabetic male Wistar rats were explanted, prepared, and immediately mounted in organ bath chambers (control group, n = 39 rings from 10 rats) or underwent 24 hours of cold ischemic preservation in saline, supplemented either with 0.5% DMSO vehicle (IR group, n = 40 rings from 10 rats) or 50 µM CANA (IR + CANA group, n = 42 rings from 11 rats). Reperfusion-induced endothelial injury was simulated by hypochlorite. Relaxation of phenylephrine precontracted aortic rings was investigated by acetylcholine (ACh), an endothelium-dependent vasorelaxant and by sodium nitroprusside (SNP), an endothelium-independent vasodilator. Additionally, we analyzed the expression of 88 genes using polymerase chain reaction (PCR) array.

Result: Impaired maximal vasorelaxation (Rmax) to ACh in the IR group compared with controls was significantly ameliorated by CANA, indicating an improvement in endothelial function (Rmax to ACh (%) control 75.2 ± 2.3 vs. IR 31.7 ± 3.2 vs. IR + CANA 51.9 ± 2.5, p < 0.05). Additionally, decreased aortic ring sensitivity (pD2-value: -log 50% maximum response) to ACh seen after IR in the vehicle group was increased by CANA (pD2 to ACh control 7.4 ± 0.1 vs. IR 6.3 ± 0.2 vs. IR + CANA 6.9 ± 0.1, p < 0.05). Although there was no difference in Rmax to SNP, the concentration–response curve in aortas from the IR + CANA group was left-shifted compared with the IR group (pD2 to SNP: control 8.7 ± 0.1 vs. IR 8.0 ± 0.1 vs. IR + CANA 8.5 ± 0.1, p < 0.05). According to the PCR array analysis, IR altered the expression of 17 genes. Compared with controls, IR upregulated the mRNA expressions of IL1a and IL6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. Furthermore, CANA prevented the upregulation of Cd40 and significantly downregulated NoxO1 gene expression.

Conclusion: Preservation of vascular grafts with CANA protects from endothelial dysfunction following IR injury. Its protective effects may be due to downregulation of proinflammatory genes and genes related to vascular injury.

Publication History

Article published online:
19 February 2021