Tuuminen Raimo, Holmström Emil, Raissadati Alireza, Saharinen Pipsa, Rouvinen Eeva, Krebs Rainer, Lemström Karl B
Transplantation Laboratory, University of Helsinki and Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
Transplantation Laboratory, University of Helsinki and Cardiac Surgery, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.
Transpl Immunol. 2016 Jul;37:40-45. doi: 10.1016/j.trim.2016.05.001. Epub 2016 May 4.
In transplantation-associated ischemia/reperfusion injury (Tx-IRI), tumor necrosis factor alpha and damage-associated molecular patterns promote caspase-8 and -9 apoptotic and receptor-interacting protein kinase-1 and -3 (RIPK1/3) necroptotic pathway activation. The extent of cell death and the counterbalance between apoptosis and regulated necrosis eventually determine the immune response of the allograft. Although simvastatin prevents Tx-IRI, its role in apoptotic and necroptotic activity remains unsolved.
Rat allograft donors and recipients were treated with a single-dose of simvastatin 2h prior to allograft procurement and reperfusion, respectively. Intragraft caspase-3, -8, and -9 and RIPK1 and -3 mRNA expression was analysed by quantitative RT-PCR and protein activity measured by immunohistochemistry and luminescent assays 6h after reperfusion. Lactate and lactate dehydrogenase (LDH) levels were analysed from allograft recipient and from hypoxic endothelial cell cultures having treated with activated simvastatin.
When compared to without cold ischemia, prolonged 4-hour cold ischemia significantly enhanced intragraft mRNA expression of caspase-3 and -9, and RIPK1 and -3, and elevated protein activity of caspase-9 and RIPK1 in the allografts. Simvastatin pretreatment decreased mRNA expression of caspase-3 and -9, and RIPK1 and -3 and protein activity of caspase-9 and RIPK1 in the allografts. Intragraft caspase-8 mRNA expression remained constant regardless of cold ischemia or simvastatin pretreatment. Simvastatin pretreatment attenuated lactate and LDH levels, both in the allograft recipients and in hypoxic endothelial cell cultures.
The beneficial effects of simvastatin pretreatment in cardiac allograft IRI may involve prevention of apoptosis and necroptosis.
在移植相关的缺血/再灌注损伤（Tx-IRI）中，肿瘤坏死因子α和损伤相关分子模式可促进半胱天冬酶-8和-9的凋亡以及受体相互作用蛋白激酶-1和-3（RIPK1/3）的坏死性凋亡途径激活。细胞死亡的程度以及凋亡与调节性坏死之间的平衡最终决定了同种异体移植物的免疫反应。尽管辛伐他汀可预防Tx-IRI，但其在凋亡和坏死性凋亡活性中的作用仍未明确。
大鼠同种异体移植供体和受体分别在同种异体移植获取和再灌注前2小时接受单剂量辛伐他汀治疗。再灌注6小时后，通过定量RT-PCR分析移植组织内半胱天冬酶-3、-8和-9以及RIPK1和-3的mRNA表达，并通过免疫组织化学和发光测定法测量蛋白活性。分析同种异体移植受体以及用活化辛伐他汀处理的缺氧内皮细胞培养物中的乳酸和乳酸脱氢酶（LDH）水平。
与无冷缺血相比，延长4小时的冷缺血显著增强了移植组织内半胱天冬酶-3和-9以及RIPK1和-3的mRNA表达，并提高了移植组织中半胱天冬酶-9和RIPK1的蛋白活性。辛伐他汀预处理降低了移植组织中半胱天冬酶-3和-9以及RIPK1和-3的mRNA表达以及半胱天冬酶-9和RIPK1的蛋白活性。无论冷缺血或辛伐他汀预处理如何，移植组织内半胱天冬酶-8的mRNA表达均保持恒定。辛伐他汀预处理降低了同种异体移植受体以及缺氧内皮细胞培养物中的乳酸和LDH水平。
辛伐他汀预处理对心脏同种异体移植IRI的有益作用可能涉及预防凋亡和坏死性凋亡。
