BACKGROUND Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury. METHODS RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively. RESULTS The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours. CONCLUSIONS Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.

中文翻译：

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“人类供体心脏的秘密生活”：冷藏期间转录组学事件的检查。

背景供体心脏的缺血耐受性对利用效率和临床结果具有重大影响。储存期间的分子事件可能会影响缺血性损伤的严重程度。方法 RNA测序用于研究组氨酸-色氨酸-酮戊二酸冷藏保存0、4、8小时后人左心室（LV，n=4）和右心室（RV，n=4）的转录谱解决方案。基因集富集分析和基因本体论分析用于检查冷藏的转录组学变化。末端脱氧核苷酸转移酶 2´-脱氧尿苷、5´-三磷酸缺口末端标记和 p65 染色分别用于检查细胞死亡和 NFκB 激活。结果 LV 显示与炎症和同种异体移植物排斥相关的基因激活，但氧化磷酸化和脂肪酸代谢途径基因下调。相反，炎症相关基因在 RV 中下调，同时氧化磷酸化基因被激活。这些转录组学变化在 8 小时时最为显着，在 0 到 4 小时之间观察到的差异要小得多。RNA 速度估计证实了免疫相关基因在储存期间在 LV 而不是在 RV 中被激活的发现。随着保存时间的增加，LV 显示 NFκB (p65) 的核转位增加，而 RV 显示靠近心内膜的细胞死亡增加，尤其是在 8 小时。结论 我们的结果表明，人类供体心脏的 LV 和 RV 对冷缺血储存有不同的反应。与炎症、氧化磷酸化和脂肪酸代谢途径以及细胞死亡和 NFκB 激活相关的转录组学变化在储存 8 小时后最为明显。