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

Bernardo, Bianca C., Nguyen, Sally S., Winbanks, Catherine E., Gao, Xiao-Ming, Boey, Esther J. H., Tham, Yow Keat, Kiriazis, Helen, Ooi, Jenny Y. Y., Porrello, Enzo R., Igoor, Sindhu, Thomas, Colleen J., Gregorevic, Paul, Lin, Ruby C. Y., Du, Xiao-Jun and McMullen, Julie R. (2014) Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. FASEB Journal, 28 12: 5097-5110. doi:10.1096/fj.14-253856


Author Bernardo, Bianca C.
Nguyen, Sally S.
Winbanks, Catherine E.
Gao, Xiao-Ming
Boey, Esther J. H.
Tham, Yow Keat
Kiriazis, Helen
Ooi, Jenny Y. Y.
Porrello, Enzo R.
Igoor, Sindhu
Thomas, Colleen J.
Gregorevic, Paul
Lin, Ruby C. Y.
Du, Xiao-Jun
McMullen, Julie R.
Title Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy
Journal name FASEB Journal   Check publisher's open access policy
ISSN 1530-6860
0892-6638
Publication date 2014-12-01
Year available 2014
Sub-type Article (original research)
DOI 10.1096/fj.14-253856
Open Access Status
Volume 28
Issue 12
Start page 5097
End page 5110
Total pages 14
Place of publication Bethesda MD, United States
Publisher Federation of American Societies for Experimental Biology
Collection year 2015
Language eng
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.—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. Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.
Keyword MicroRNAs
Pressure overload
Heart failure
LNA-therapeutics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 15 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 15 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 06 Jan 2015, 00:31:11 EST by System User on behalf of School of Biomedical Sciences