Publication Date:
2013-02-22
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boon, Reinier A -- Iekushi, Kazuma -- Lechner, Stefanie -- Seeger, Timon -- Fischer, Ariane -- Heydt, Susanne -- Kaluza, David -- Treguer, Karine -- Carmona, Guillaume -- Bonauer, Angelika -- Horrevoets, Anton J G -- Didier, Nathalie -- Girmatsion, Zenawit -- Biliczki, Peter -- Ehrlich, Joachim R -- Katus, Hugo A -- Muller, Oliver J -- Potente, Michael -- Zeiher, Andreas M -- Hermeking, Heiko -- Dimmeler, Stefanie -- England -- Nature. 2013 Mar 7;495(7439):107-10. doi: 10.1038/nature11919. Epub 2013 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23426265" target="_blank"〉PubMed〈/a〉
Keywords:
Aging/genetics/pathology/*physiology
;
Animals
;
Apoptosis
;
DNA Damage
;
Fibrosis/genetics/pathology
;
Gene Deletion
;
*Gene Expression Regulation
;
Gene Knockout Techniques
;
Genetic Therapy
;
Heart/*physiology
;
Mice
;
Mice, Inbred C57BL
;
MicroRNAs/*genetics/metabolism
;
Myocardial Infarction/genetics/pathology/therapy
;
Myocardium/cytology/*metabolism/pathology
;
Myocytes, Cardiac/cytology/metabolism/pathology
;
Substrate Specificity
;
Telomere/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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