The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function
Open accessAbstract
MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (MI) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to MI was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the MI model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca 2+ ATPase gene expression. Improved outcome in LNA-antimiR-34–treated MI and TAC mice was accompanied by up-regulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O -fucosyltranferase 1, Notch1, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of disease-implicated miRNA seed families.
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Self-citationPervasive roles of microRNAs in cardiovascular biology
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Self-citationMicroRNAs in the Human Heart: A Clue to Fetal Gene Reprogramming in Heart Failure
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Self-citationSilencing of microRNA families by seed-targeting tiny LNAs
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Noncoding RNA therapeutics—Challenges and potential solutions
Winkle, M., El-Daly, S. M., Fabbri, M., & Calin, G. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00219-z · Cited by 1,551
MicroRNA-34a regulates cardiac ageing and function.
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Development of microRNA therapeutics is coming of age
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Adult-specific functions of animal microRNAs
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Metadata
- Authors
- Bernardo, B. C., Gao, X.-M., Winbanks, C. E., Boey, E. J. H., Tham, Y. K., Kiriazis, H., Gregorevic, P., Obad, S., Kauppinen, S., Du, X.-J., Lin, R. C. Y., & McMullen, J. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2012-10-09
- Volume
- 109
- Issue
- 43
- Pages
- 17615-17620
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2155794059
- Cited by
- 429
- References
- 39
- FWCI
- 19.18
- Type
- journal article
- Language
- en
- Open access
- green
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- Bernardo, B. C., Gao, X.-M., Winbanks, C. E., Boey, E. J. H., Tham, Y. K., Kiriazis, H., Gregorevic, P., Obad, S., Kauppinen, S., Du, X.-J., Lin, R. C. Y., & McMullen, J. R. (2012). Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1206432109
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