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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682232.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
MicroRNA-34a regulates cardiac ageing and function
Authors:Boon, R. A.; Iekushi, K.; Lechner, S.; Seeger, T.; Fischer, A.; Heydt, S.; Kaluza, D.; Treguer, K.; Carmona, G.; Bonauer, A.; Horrevoets, A. J.; Didier, N.; Girmatsion, Z.; Biliczki, P.; Ehrlich, J. R.; Katus, H. A.; Muller, O. J.; Potente, M.; Zeiher, A. M.; Hermeking, H.; Dimmeler, S.
Date of Publication (YYYY-MM-DD):2013-03-07
Journal Abbrev.:Nature
Issue / Number:7439
Start Page:107
End Page:110
Audience:Not Specified
Abstract / 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.
Free 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
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%W NLM %G eng
Identifiers:ISSN:0028-0836 %R 10.1038/nature11919
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