MicroRNA-34a regulates cardiac ageing and function

Reinier A. Boon, Kazuma Iekushi, Stefanie Lechner, Timon Seeger, Ariane Fischer, Susanne Heydt, David Kaluza, Karine Tréguer, Guillaume Carmona, Angelika Bonauer, Anton J.G. Horrevoets, Nathalie Didier, Zenawit Girmatsion, Peter Biliczki, Joachim R. Ehrlich, Hugo A. Katus, Oliver J. Müller, Michael Potente, Andreas M. Zeiher, Heiko HermekingStefanie Dimmeler

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485 Citations (Scopus)

Abstract

Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

Original languageEnglish
Pages (from-to)107-110
Number of pages4
JournalNature
Volume495
Issue number7439
DOIs
Publication statusPublished - Mar 2013

ASJC Scopus subject areas

  • General

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    Boon, R. A., Iekushi, K., Lechner, S., Seeger, T., Fischer, A., Heydt, S., Kaluza, D., Tréguer, K., Carmona, G., Bonauer, A., Horrevoets, A. J. G., Didier, N., Girmatsion, Z., Biliczki, P., Ehrlich, J. R., Katus, H. A., Müller, O. J., Potente, M., Zeiher, A. M., ... Dimmeler, S. (2013). MicroRNA-34a regulates cardiac ageing and function. Nature, 495(7439), 107-110. https://doi.org/10.1038/nature11919