Department of Cardiac Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary.
Int J Mol Sci. 2021 Jul 21;22(15):7774. doi: 10.3390/ijms22157774.
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%, < 0.05). IR altered the expression of 17 genes. , , , , , , , and have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of and , 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.
血管缺血/再灌注损伤（IRI）是导致冠状动脉旁路移植术后移植物失败和不良临床结局的原因之一。钠-葡萄糖共转运蛋白（SGLT）-2 抑制剂已被证明可预防心肌 IRI，无论是否患有糖尿病。我们假设在生理盐水基础上加用卡格列净（SGLT-2 抑制剂）可以保护血管移植物免受 IRI。从非糖尿病大鼠中分离出主动脉环，并立即将其安装在器官浴槽室中（对照组，n = 9-10 只大鼠）或在生理盐水中进行冷缺血保存，补充 DMSO 载体（IR 组，n = 8-10 只大鼠）或 50µM 卡格列净（IR + CANA 组，n = 9-11 只大鼠）。测量血管功能，使用 PCR 阵列分析 88 个基因的表达，并应用机器学习进行特征选择。与对照组相比，IR 组乙酰胆碱诱导的最大血管舒张功能受损，CANA 显著改善（IR 组 31.7 ± 3.2% vs. IR + CANA 组 51.9 ± 2.5%，<0.05）。IR 改变了 17 个基因的表达。 、 、 、 、 、 、 和 被发现具有最高的相互作用。与对照组相比，IR 显著上调了 和 的 mRNA 表达，CANA 分别将其下调了 1.5-和 1.75 倍。CANA 可显著预防 Cd40 的上调，下调 NoxO1 基因表达，减少 ICAM-1 和硝基酪氨酸，并增加 PECAM-1 免疫反应性。CANA 可减轻 IRI 后的内皮功能障碍。
