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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 Extracellular Vesicles”

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.122.061834Circulation. 2023;147:e64–e65

    To the Editor:

    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

    Footnotes

    Circulation is available at www.ahajournals.org/journal/circ

    REFERENCES

    • 1. Hosen MR, Goody PR, Zietzer A, Xiang X, Niepmann ST, Sedaghat A, Tiyerili V, Chennupati R, Moore JB, Boon RA, et al. 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 extracellular vesicles.Circulation. 2022; 146:1836–1854. doi: 10.1161/CIRCULATIONAHA.122.060258LinkGoogle Scholar
    • 2. McCall MN, Kim MS, Adil M, Patil AH, Lu Y, Mitchell CJ, Leal-Rojas P, Xu J, Kumar M, Dawson VL, et al. Towards the human cellular microRNAome.Genome Res. 2017; 27:1769–1781. doi: 10.1101/gr.222067.117CrossrefMedlineGoogle Scholar
    • 3. Wei Z, Batagov AO, Carter DRF, Krichevsky AM. Fetal bovine serum RNA interferes with the cell culture derived extracellular RNA.Sci Rep. 2016; 6:31175. doi: 10.1038/srep31175CrossrefMedlineGoogle Scholar
    • 4. Xanthopoulos A, Starling RC, Kitai T, Triposkiadis F. Heart failure and liver disease: cardiohepatic interactions.JACC Heart Fail. 2019; 7:87–97. doi: 10.1016/j.jchf.2018.10.007CrossrefMedlineGoogle Scholar
    • 5. Albanese M, Chen YA, Hüls C, Gärtner K, Tagawa T, Mejias-Perez E, Keppler OT, Göbel C, Zeidler R, Shein M, et al. MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells.PLoS Genet. 2021; 17:e1009951. doi: 10.1371/journal.pgen.1009951CrossrefMedlineGoogle Scholar

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