Lukac Jan, Dhaygude Kishor, Saraswat Mayank, Joenväärä Sakari, Syrjälä Simo O, Holmström Emil J, Krebs Rainer, Renkonen Risto, Nykänen Antti I, Lemström Karl B
Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland; Department of Cardiothoracic Surgery, University Hospital Cologne and University of Cologne, Germany.
Translational Immunology Research Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
J Heart Lung Transplant. 2022 Mar;41(3):311-324. doi: 10.1016/j.healun.2021.11.011. Epub 2021 Nov 25.
The pathophysiological changes related to brain death may affect the quality of the transplanted organs and expose the recipients to risks. We probed systemic changes reflected in donor plasma proteome and investigated their relationship to heart transplant outcomes.
Plasma samples from brain-dead multi-organ donors were analyzed by label-free protein quantification using high-definition mass spectrometry. Unsupervised and supervised statistical models were used to determine proteome differences between brain-dead donors and healthy controls. Proteome variation and the corresponding biological pathways were analyzed and correlated with transplant outcomes.
Statistical models revealed that donors had a unique but heterogeneous plasma proteome with 237 of 463 proteins being changed compared to controls. Pathway analysis showed that coagulation, gluconeogenesis, and glycolysis pathways were upregulated in donors, while complement, LXR/RXR activation, and production of nitric oxide and reactive oxygen species in macrophages pathways were downregulated. In point-biserial correlation analysis, lysine-specific demethylase 3A was moderately correlated with any grade and severe PGD. In univariate and multivariate Cox regression analyses myosin Va and proteasome activator complex subunit 2 were significantly associated with the development of acute rejections with hemodynamic compromise within 30 days. Finally, we found that elevated levels of lysine-specific demethylase 3A and moesin were identified as predictors for graft-related 1-year mortality in univariate analysis.
We show that brain death significantly changed plasma proteome signature Donor plasma protein changes related to endothelial cell and cardiomyocyte function, inflammation, and vascular growth and arteriogenesis could predict transplant outcome suggesting a role in donor evaluation.
与脑死亡相关的病理生理变化可能会影响移植器官的质量，并使接受者面临风险。我们探究了供体血浆蛋白质组中反映的全身变化，并研究了它们与心脏移植结果的关系。
使用高清质谱通过无标记蛋白质定量分析脑死亡多器官供体的血浆样本。使用无监督和有监督的统计模型来确定脑死亡供体与健康对照之间的蛋白质组差异。分析蛋白质组变异及其相应的生物学途径，并将其与移植结果相关联。
统计模型显示，供体具有独特但异质性的血浆蛋白质组，与对照组相比，463种蛋白质中有237种发生了变化。通路分析表明，供体中凝血、糖异生和糖酵解通路上调，而补体、LXR/RXR激活以及巨噬细胞中一氧化氮和活性氧的产生通路下调。在点二列相关分析中，赖氨酸特异性去甲基化酶3A与任何等级和严重的原发性移植肝无功能呈中度相关。在单变量和多变量Cox回归分析中，肌球蛋白Va和蛋白酶体激活复合物亚基2与30天内出现血流动力学受损的急性排斥反应的发生显著相关。最后，我们发现在单变量分析中，赖氨酸特异性去甲基化酶3A和埃兹蛋白水平升高被确定为移植物相关1年死亡率的预测指标。
我们表明脑死亡显著改变了血浆蛋白质组特征。与内皮细胞和心肌细胞功能、炎症以及血管生长和动脉生成相关的供体血浆蛋白变化可以预测移植结果，提示其在供体评估中的作用。
