Journal
NATURE
Volume 495, Issue 7439, Pages 107-110Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11919
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Funding
- Netherlands Organization for Scientific Research (NWO)
- Japanese Heart Foundation
- Excellence Cluster Cardiopulmonary System [Exc 147-1]
- European Research Council
- German Center for Cardiovascular Research DZHK
- European Union [241440]
- German Centre for Cardiovascular Research (DZHK)
- German Ministry of Education and Research (BMBF)
- ERC
- DFG
- Deutsche Krebshilfe
- Rudolf-Bartling-Stiftung
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Ageing is the predominant risk factor for cardiovascular diseases(1) and contributes to a significantly worse outcome in patients with acute myocardial infarction(2). MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing(3,4). 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.
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