Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FIN-00014, University of Helsinki, Helsinki, Finland.
Circulation. 2011 Sep 6;124(10):1138-50. doi: 10.1161/CIRCULATIONAHA.110.005249. Epub 2011 Aug 15.
Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection.
Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-β1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-β1-induced microvascular endothelial-to-mesenchymal transition.
Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.
缺血/再灌注损伤可能对心脏移植物产生有害的短期和长期后果。其潜在机制涉及微血管功能障碍，最终可能导致原发性移植物衰竭或无法治疗的慢性排斥反应。
在这里，我们报告说，大鼠心脏移植物缺血/再灌注损伤导致严重的微血管功能障碍，而供体在获取移植物前 2 小时口服单剂量辛伐他汀（3-羟基-3-甲基戊二酰辅酶 A 还原酶和 Rho GTPase 抑制剂）可预防这种损伤。在移植物保存期间，供体辛伐他汀治疗抑制微血管内皮细胞和周细胞 RhoA/Rho 相关蛋白激酶的激活和内皮细胞-内皮细胞间隙的形成；降低移植内缺氧诱导因子-1α、诱导型一氧化氮合酶和内皮素-1 的 mRNA 水平；并增加血红素加氧酶-1。供体而非受体的辛伐他汀治疗可预防缺血/再灌注损伤诱导的血管渗漏、白细胞浸润、无复流现象和心肌损伤。辛伐他汀对血管稳定性和无复流现象的有益作用分别被一氧化氮合酶抑制剂 N-硝基-L-精氨酸甲酯和 geranylgeranyl pyrophosphate 补充 RhoA 激活所废除。在慢性排斥反应模型中，供体辛伐他汀治疗抑制心脏移植物炎症、转化生长因子-β1 信号和心肌纤维化。在体外，辛伐他汀抑制转化生长因子-β1 诱导的微血管内皮细胞向间充质转化。
我们的结果表明，供体辛伐他汀治疗可预防微血管内皮细胞和周细胞功能障碍、缺血/再灌注损伤和慢性排斥反应，并为保护心脏移植物提供了一种新颖的、可行的临床策略。
