title: MicroRNA-34a regulates cardiac ageing and function.
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.
authors: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany.
authors: Reinier A
authors: RA
authors: Boon
authors: Kazuma
authors: K
authors: Iekushi
authors: Stefanie
authors: S
authors: Lechner
authors: Timon
authors: T
authors: Seeger
authors: Ariane
authors: A
authors: Fischer
authors: Susanne
authors: S
authors: Heydt
authors: David
authors: D
authors: Kaluza
authors: Karine
authors: K
authors: Tréguer
authors: Guillaume
authors: G
authors: Carmona
authors: Angelika
authors: A
authors: Bonauer
authors: Anton J G
authors: AJ
authors: Horrevoets
authors: Nathalie
authors: N
authors: Didier
authors: Zenawit
authors: Z
authors: Girmatsion
authors: Peter
authors: P
authors: Biliczki
authors: Joachim R
authors: JR
authors: Ehrlich
authors: Hugo A
authors: HA
authors: Katus
authors: Oliver J
authors: OJ
authors: Müller
authors: Michael
authors: M
authors: Potente
authors: Andreas M
authors: AM
authors: Zeiher
authors: Heiko
authors: H
authors: Hermeking
authors: Stefanie
authors: S
authors: Dimmeler
mesh_terms: D000375:Aging / Q000235:genetics / Q000473:pathology / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D015316:Genetic Therapy; D006321:Heart / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D016615:Telomere / Q000235:genetics / Q000378:metabolism
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs