Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy

Bianca C Bernardo, Sally S Nguyen, Catherine E Winbanks, Xiao-Ming Gao, Esther J H Boey, Yow Keat Tham, Helen Kiriazis, Jenny Y.Y. Ooi, Enzo R Porrello, Sindhu Igoor, Colleen J. Thomas, Paul Gregorevic, Ruby C Y Lin, Xiao Jun Du, Julie R. McMullen

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48 Citations (Scopus)

Abstract

Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.

Original languageEnglish
Pages (from-to)5097-5110
Number of pages14
JournalThe FASEB Journal
Volume28
Issue number12
DOIs
Publication statusPublished - 1 Dec 2014
Externally publishedYes

Keywords

  • Heart failure
  • LNA-therapeutics
  • MicroRNAs
  • Pressure overload

Cite this

Bernardo, B. C., Nguyen, S. S., Winbanks, C. E., Gao, X-M., Boey, E. J. H., Tham, Y. K., Kiriazis, H., Ooi, J. Y. Y., Porrello, E. R., Igoor, S., Thomas, C. J., Gregorevic, P., Lin, R. C. Y., Du, X. J., & McMullen, J. R. (2014). Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. The FASEB Journal, 28(12), 5097-5110. https://doi.org/10.1096/fj.14-253856