Romero Erick, Chang Eleanor, Tabak Esteban, Pinheiro Diego, Tallaj Jose, Litovsky Silvio, Keating Brendan, Deng Mario, Cadeiras Martin
Division of Cardiovascular Medicine, UC Davis Medical Center, Sacramento, CA.
Division of Cardiology, UCLA Medical Center, Los Angeles, CA.
Transplant Direct. 2020 Oct 19;6(11):e616. doi: 10.1097/TXD.0000000000001065. eCollection 2020 Nov.
Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs.
We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters.
The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis-derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules.
During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.
线粒体功能障碍与移植器官预后不良相关。心内膜心肌活检（EMB）中线粒体相关基因表达（GE）可作为排斥反应的非免疫功能标志物。我们假设急性心脏移植排斥反应与EMB中线粒体相关GE降低有关。
我们收集了47例心脏移植术后患者的64份常规或临床指征性EMB。对EMB进行mRNA测序。我们进行了加权基因共表达网络分析以构建模块衍生的特征基因。通过基因本体富集和中心基因分析对模块进行评估。根据国际心肺移植学会基于组织学的标准以及仅基于GE的分类，将模块与EMB相关联；我们还将其与临床参数相关联。
富含线粒体相关和免疫反应基因的模块与临床特征的相关性最强。与无排斥反应样本相比，排斥反应样本中线粒体相关基因的活性降低，免疫反应基因的活性增加。线粒体相关模块中的生物学过程和中心基因主要涉及能量产生、底物代谢和氧化应激调节。与国际心肺移植学会标准相比，基于GE的分类与加权基因共表达网络分析衍生的功能模块的相关性更强。脑钠肽水平、免疫状态检测（ImmuKnow）和Allomap评分与线粒体相关模块的表达呈负相关，与免疫反应模块呈正相关。
在急性心脏移植排斥反应期间，线粒体相关基因的活性降低，这与免疫反应基因的活性增加以及脑钠肽升高所表现出的移植器官功能受损有关。这表明存在与排斥反应相关的线粒体损伤。
