Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Pharmacology, Hangzhou Medical College, Hangzhou 310053, China.
Life Sci. 2018 Oct 1;210:47-54. doi: 10.1016/j.lfs.2018.08.062. Epub 2018 Aug 28.
To determine whether linagliptin, a dipeptidyl peptidase 4 inhibitor, can promote the recovery of cardiac function after hypothermic preservation.
Rat hearts were preserved in cold Celsior solution with or without linagliptin for 9 h. Cardiac function was evaluated at 60 min of reperfusion after hypothermic preservation. Cardiac mitochondrial morphology was observed using transmission electron microscope. The expression of dynamin-related protein 1 (Drp1), NADPH oxidase 2 (NOX2), calmodulin-dependent protein kinase II (CaMKII) were detected using Western blot.
Compared with Celsior group, supplement of Celsior solution with linagliptin (0.25-0.75 nM) could significantly prevent hypothermic preservation-induced cardiac dysfunction. The expression of NOX2 protein, ROS level and MDA content in cardium were increased after hypothermic preservation, which was inhibited by linagliptin. Although the mitofusin1, 2, optic atrophy type 1, and total Drp1 expression in myocardium did not change, the level of p-Drp1 S616 and mitochondrial Drp1 were enhanced after hypothermic preservation. Linagliptin supplement could inhibit the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein, and mitigate the mitochondrial fragmentation. Level of p-CaMKII protein enhanced after hypothermic preservation, which could be prevented by linagliptin or a NOX2 inhibitor Phox-I2. Both Phox-I2 and a CaMKII inhibitor KN-93 could reduce the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein.
Supplement Celsior solution with linagliptin could improve cardiac function recovery in 9-h hypothermic preserved rat hearts. The cardioprotective effect of linagliptin might be due to the inhibition of Drp1 phosphorylation and mitochondrial translocation by preventing NOX2-mediated CaMKII activation.
确定二肽基肽酶 4 抑制剂利拉利汀是否能促进低温保存后心脏功能的恢复。
用含或不含利拉利汀的冷 Celsior 溶液保存大鼠心脏 9 小时。低温保存后再灌注 60 分钟时评估心脏功能。用透射电镜观察心脏线粒体形态。用 Western blot 检测动力相关蛋白 1（Drp1）、NADPH 氧化酶 2（NOX2）、钙调蛋白依赖性蛋白激酶 II（CaMKII）的表达。
与 Celsior 组相比，Celsior 溶液中添加 0.25-0.75 nM 的利拉利汀能显著防止低温保存引起的心脏功能障碍。低温保存后心脏组织中 NOX2 蛋白表达、ROS 水平和 MDA 含量增加，利拉利汀可抑制其增加。低温保存后心肌中线粒体融合蛋白 1、2、视神经萎缩 1 和总 Drp1 表达无变化，但 p-Drp1 S616 和线粒体 Drp1 水平增加。利拉利汀补充可抑制低温保存引起的 p-Drp1 S616 和线粒体 Drp1 蛋白增加，减轻线粒体碎片化。低温保存后 p-CaMKII 蛋白水平升高，利拉利汀或 NOX2 抑制剂 Phox-I2 可预防其升高。Phox-I2 和 CaMKII 抑制剂 KN-93 均可减少低温保存引起的 p-Drp1 S616 和线粒体 Drp1 蛋白增加。
补充 Celsior 溶液中的利拉利汀可改善 9 小时低温保存大鼠心脏的功能恢复。利拉利汀的心脏保护作用可能是通过抑制 NOX2 介导的 CaMKII 激活来抑制 Drp1 磷酸化和线粒体易位。
