Garcia Nahuel Aquiles, Moncayo-Arlandi Javier, Vazquez Alejandro, Genovés Patricia, Calvo Conrado J, Millet José, Martí Nuria, Aguado Carmen, Knecht Erwin, Valiente-Alandi Iñigo, Montero José A, Díez-Juan Antonio, Sepúlveda Pilar
Mixed Unit for Cardiovascular Repair, Institute of Sanitary Research La Fe-Príncipe Felipe Research Center, Valencia, Spain.
Cardiovascular Genetics Center, Institute for Biomedical investigation Girona, Girona, Spain.
Ann Transplant. 2017 May 9;22:285-295. doi: 10.12659/aot.901410.
BACKGROUND Cardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac cell culture and its potential therapeutic use in combination with cardioplegia formulations. MATERIAL AND METHODS We added hydrogen sulfide donor GYY4137 to HL-1 cells to study its protective effect in nutrient starved conditions. In addition, we tested the potential use of GYY4137 when it is added into two different cardioplegia formulations: Cardi-Braun® solution and del Nido solution in an ex vivo Langendorff perfused rat hearts model. RESULTS We observed that eight-hour pre-treatment with GYY4137 significantly suppressed apoptosis in nutrient-starved HL-1 cells (28% less compared to untreated cells; p<0.05), maintained ATP content, and reduced protein synthesis. In ex vivo experiments, Cardi-Braun® and del Nido cardioplegia solutions supplemented with GYY4137 significantly reduced the pro-apoptotic protein caspase-3 content and preserved ATP content. Furthermore, GYY4137 supplemented cardioplegia solutions decreased the S-(5-adenosyl)-L-methionine/S-(adenosyl)-L-homocysteine ratio, reducing the oxidative stress in cardiac tissue. Finally, heart beating analysis revealed the preservation of the inter-beat interval and the heart rate in del Nido cardioplegia solution supplemented with GYY4137. CONCLUSIONS GYY4137 preconditioning preserved energetic state during starved conditions, attenuating the cardiomyocytes apoptosis in vitro. The addition of GYY4137 to cardioplegia solutions prevented apoptosis, ATP consumption, and oxidative stress in perfused rat hearts, restoring its electrophysiological status after cardiac arrest. These findings suggested that GYY4137 sulfide donor may improve the cardioplegia solution performance during cardiac surgery.
背景 心脏停搏是多种心脏手术中常用的操作，人们提出了不同的配方以增强其心脏保护作用。硫化氢是一种具有心脏保护特性的重要信号分子。因此，我们研究了硫化氢在心脏细胞培养中的心脏保护作用及其与心脏停搏液配方联合使用的潜在治疗用途。
材料与方法 我们将硫化氢供体GYY4137添加到HL-1细胞中，以研究其在营养饥饿条件下的保护作用。此外，我们在离体Langendorff灌注大鼠心脏模型中测试了将GYY4137添加到两种不同心脏停搏液配方（Cardi-Braun®溶液和del Nido溶液）中的潜在用途。
结果 我们观察到，用GYY4137预处理8小时可显著抑制营养饥饿的HL-1细胞中的凋亡（与未处理细胞相比减少28%；p<0.05），维持ATP含量，并减少蛋白质合成。在离体实验中，添加GYY4137的Cardi-Braun®和del Nido心脏停搏液显著降低促凋亡蛋白caspase-3含量并保留ATP含量。此外，添加GYY4137的心脏停搏液降低了S-(5-腺苷)-L-甲硫氨酸/S-(腺苷)-L-高半胱氨酸比率，减轻了心脏组织中的氧化应激。最后，心跳分析显示，添加GYY4137的del Nido心脏停搏液中的心搏间期和心率得以保留。
结论 GYY4137预处理在饥饿条件下保留了能量状态，减轻了体外心肌细胞凋亡。在心脏停搏液中添加GYY4137可防止灌注大鼠心脏中的凋亡、ATP消耗和氧化应激，恢复心脏骤停后的电生理状态。这些发现表明，GYY4137硫化物供体可能会改善心脏手术期间心脏停搏液的性能。
