Letter by Halushka and Witwer Regarding Article, "Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellula
Letter by Halushka and Witwer Regarding Article, "Circulating MicroRNA-122-5p Is Associated With a Lack of Improvement in Left Ventricular Function After Transcatheter Aortic Valve Replacement and Regulates Viability of Cardiomyocytes Through Extracellula
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Halushka 和 Witwer 关于文章“循环 MicroRNA-122-5p 与经导管主动脉瓣置换术后左心室功能缺乏改善有关，并通过细胞外调节心肌细胞的活力”的信函
DOI：
10.1161/circulationaha.122.061834
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发表时间：
2023
期刊：
影响因子：
37.8
通讯作者：
Witwer,KennethW
中科院分区：
文献类型：
--
作者：
Halushka,MarcK;Witwer,KennethW
Hosen等人的文章1表明miR-122-5p是经导管主动脉瓣置换术后左心室功能改善失败的生物标志物。在心脏中miR-122-5p的其他功能研究中，细胞外囊泡（EV）将miR-122-5p从生理上转染的内皮细胞递送到受体心肌细胞，可能通过BCL-2机制导致心肌细胞活力下降和细胞凋亡增加。所有基因、蛋白质和microRNA实验的首要原则是确定这些部分相对于被询问的细胞和组织的定位。例如，人们不会探索titin在淋巴细胞中的机械活性。microrna的通用数字命名法（如miR-141、miR-142、miR-143、miR-144）往往隐藏了特定的细胞表达模式。在所有无偏倚的组织和细胞数据集中，miR-122-5p在肝细胞中特异性和高表达。2无偏倚的microRNA图谱表明，miR-122-5p在内皮细胞、心肌细胞或瓣膜组织中没有显著的原生表达。这些图谱显示，miR-122-5p位于血液（血浆、血清）中，可能是因为EV或肝细胞释放的游离miR-122-5p。这与miR-122-5p是细胞培养中使用的胎牛血清中已知的丰富污染物有关。3事实上，在细胞培养ev相关实验中，miR-122-5p经常被鉴定为差异表达。由于miR-122-5p定位于肝脏而不是心脏，因此必须谨慎地以新的角度解释本文的实验。尽管miR-122-5p生物标志物数据很有趣，但对这些数据的适当解释是，作者发现了继发于心功能不良的肝衰竭标志物。有大量文献表明，miR-122-5p升高既是肝脏疾病（如丙型肝炎病毒、非酒精性脂肪性肝病、药物性肝损伤）的主要生物标志物，也是引起继发性肝脏疾病（如败血症、心脏损伤）的疾病过程的生物标志物。miR-122-5p可以被认为是丙氨酸转氨酶/天冬氨酸转氨酶的等效测量。因此，miR-122-5p不太可能成为经导管主动脉瓣置换术相关结果的特定、有用的生物标志物，因为其升高有许多原因，并且存在等效的生物标志物。由于miR-122-5p不是内皮细胞的天然产物，因此很难理解功能实验的生物学相关性。尽管如此，有一项发现可能意义重大。与先前证明表达miR-122-5p的转基因心脏引起心肌细胞凋亡的工作一致，本文作者表明miR-122-5p的EV穿梭诱导了相同的发现。从生物学上讲，ev包膜的miR-122-5p不会来自内皮细胞，但它可能通过循环的肝细胞ev到达心脏。因此，心肌细胞凋亡和活力的研究可能为了解肝硬化心肌病提供新的途径。这将需要进一步的仔细研究，以确定是否有足够的肝细胞来源的miR-122-5p被心肌细胞吸收以发挥功能，特别是考虑到最近的报道，ev的microRNA转移可能不像以前假设的那样普遍或有效。5
The article by Hosen et al1 indicates that miR-122-5p is a biomarker of the failed improvement of left ventricular function after transcatheter aortic valve replacement. Among additional functional studies of miR-122-5p in the heart, the extracellular vesicle (EV) delivery of miR-122-5p from supraphysiologically transfected endothelial cells into recipient cardiomyocytes caused decreased cardiomyocyte viability and increased apoptosis, potentially through a BCL-2 mechanism. A first principle of all gene, protein, and microRNA experiments is to establish the localization of these moieties relative to the cells and tissues being interrogated. One would not explore mechanical activities of titin in lymphocytes, for example. The generic numerical nomenclature of microRNAs (eg, miR-141, miR-142, miR-143, miR-144) often hides specific cellular expression patterns. miR-122-5p is, across all unbiased tissue and cellular datasets, specifically and highly expressed by liver hepatocytes. 2 Unbiased microRNA atlases indicate that miR-122-5p is not meaningfully expressed natively in endothelial cells, cardiomyocytes, or valve tissues. These same atlases show that miR-122-5p is located in blood fluids (plasma, serum), likely because of EV or free miR-122-5p released from hepatocytes. This correlates with miR-122-5p being a known abundant contaminant of fetal bovine serum used in cell culture. 3 In fact, miR-122-5p is frequently identified as differentially expressed in cell culture EV-related experiments. With the localization of miR-122-5p to the liver and not the heart, the experiments of the article must be interpreted with caution and in a new light. Although the miR-122-5p biomarker data are intriguing, the appropriate interpretation of the data is that the authors found a marker of liver failure secondary to poor cardiac function. 4 There is a clear body of literature indicating elevated miR-122-5p as both a primary biomarker of liver diseases (eg, hepatitis C virus, nonalcoholic fatty liver disease, drug-induced liver injury) and as a biomarker of disease processes causing secondary liver disease (eg, sepsis, heart injury). miR-122-5p can be thought of as an alanine aminotransaminase/aspartate transaminase-equivalent measure. Thus, it is unlikely that miR-122-5p will ever be a specific, useful biomarker for transcatheter aortic valve replacement–related outcomes because its elevation will have many causes and because equivalent biomarkers exist.Because miR-122-5p is not native to endothelial cells, it is difficult to understand the biological relevance of the functional experiments. Despite this, one finding may be of significance. Consistent with previous work demonstrating transgenic hearts that express miR-122-5p caused cardiomyocyte apoptosis, here the authors show EV shuttling of miR-122-5p inducing the same finding. Biologically, EV-encapsulated miR-122-5p would not be coming from endothelial cells, but it could be arriving in the heart through circulating hepatocyte EVs. Thus, the cardiomyocyte apoptosis and viability studies may provide a new pathway to understand cirrhotic cardiomyopathy. 4 This will require further, careful study to determine whether enough hepatocyte-derived miR-122-5p is taken up by cardiomyocytes to be functional, especially in light of recent reports that microRNA transfer by EVs may not be as ubiquitous or efficient as previously assumed. 5