Center for Medical Genomics OMICRON, Jagiellonian University Medical College, ul. Kopernika 7C, 31-034, Krakow, Poland.
Department of Rheumatology, Jagiellonian University Medical College, Krakow, Poland.
Mol Med. 2022 Dec 14;28(1):156. doi: 10.1186/s10020-022-00588-0.
The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies.
We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors and 61 healthy controls (254 samples in total). We then analyzed processes regulated by differentially expressed circulating miRNAs and cross-validated results with the data of patients with clinically manifested cardiomyopathies.
We found that especially miRNAs contained within EVs may be informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin signaling, transforming growth factor beta (TGFβ) or epidermal growth factor receptors (ErbB). We identified vesicular miR-144-3p and miR-423-3p as the most variable between groups and significantly correlated with echocardiographic parameters and, respectively, for plasma: let-7g-5p and miR-16-2-3p. Moreover, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is differentially expressed in the circulation of patients with dilated cardiomyopathy. We also found that distribution of particular miRNAs between of plasma and EVs (proportion between compartments) e.g., miR-184 in ALL, is altered, suggesting changes within secretory and miRNA sorting mechanisms.
Our results show that transcriptomic changes resulting from doxorubicin induced myocardial injury are reflected in circulating miRNA levels and precede development of the late onset cardiomyopathy phenotype. Among miRNAs related to cardiac function, we found vesicular miR-144-3p and miR-423-3p, as well as let-7g-5p and miR-16-2-3p contained in the total plasma. Selection of source for such studies (plasma or EVs) is of critical importance, as distribution of some miRNA between plasma and EVs is altered in ALL survivors, in comparison to healthy people, which suggests that doxorubicin-induced changes include miRNA sorting and export to extracellular space.
阿霉素的使用与急性和长期心肌病的风险增加有关。尽管癌症幸存者的数量不断增加，但对于导致严重心脏结局的时间相关转录机制知之甚少。也不清楚与阿霉素使用相关的长期转录组改变是否与患有其他心肌病的患者的转录组模式相似。
我们对 66 名急性淋巴细胞白血病 (ALL) 幸存者和 61 名健康对照者（共 254 个样本）的总血浆和细胞外囊泡 (EV) 中的 miRNA 进行了测序。然后，我们分析了差异表达的循环 miRNA 调节的过程，并与临床表现为心肌病的患者的数据进行了交叉验证。
我们发现，特别是 EV 中包含的 miRNA 在心肌病发展方面可能具有信息性，并且可能调节与神经营养因子信号、转化生长因子β (TGFβ) 或表皮生长因子受体 (ErbB) 相关的途径。我们发现囊泡 miR-144-3p 和 miR-423-3p 是组间最具变异性的 miRNA，与超声心动图参数显著相关，而血浆中的分别为 let-7g-5p 和 miR-16-2-3p。此外，囊泡 miR-144-3p 与最多数量的超声心动图参数相关，并且在扩张型心肌病患者的循环中表达不同。我们还发现，特定 miRNA 在血浆和 EV 之间的分布（隔室之间的比例），例如 ALL 中的 miR-184，发生改变，提示分泌和 miRNA 分选机制发生变化。
我们的结果表明，阿霉素诱导的心肌损伤导致的转录组变化反映在循环 miRNA 水平上，并先于晚期发病心肌病表型的发展。在与心脏功能相关的 miRNA 中，我们发现了囊泡 miR-144-3p 和 miR-423-3p，以及总血浆中的 let-7g-5p 和 miR-16-2-3p。此类研究中源的选择（血浆或 EVs）至关重要，因为与健康人相比，ALL 幸存者中一些 miRNA 在血浆和 EVs 之间的分布发生改变，这表明阿霉素诱导的变化包括 miRNA 分选和向细胞外空间的输出。
