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.
