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MicroRNA-34a is a pivotal age-induced regulator of cardiac apoptosis, telomere maintenance and contractile function: Implications for therapeutic inhibition

Prevention


Reinier Boon

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List of Authors: Reinier A. Boon,a Kazuma Iekushi,a Stefanie Lechner,c Ariane Fischer,a Susanne Heydt,a Karine Tréguer,a Guillaume Carmona,a Angelika Bonauer,a Anton J.G. Horrevoets,d Zenawit Girmatsion,b Peter Biliczki,b Joachim R. Ehrlich,b Hugo A. Katus,e Oliver J Müller,e Michael Potente,a,b Andreas M. Zeiher,b Heiko Hermekingc and Stefanie Dimmelera
From the Institute for Cardiovascular Regeneration,a Centre of Molecular Medicine; the Department of Cardiology,b Internal Medicine III, Goethe University, Frankfurt;Experimental and Molecular Pathology,c Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany; and the Department of Molecular Cell Biology and Immunology,d VU University Medical Center, Amsterdam, the Netherlands; Internal Medicine III,e Heidelberg Universiy Hospital, Heidelberg, Germany

Abstract:

Background
Aging is the major risk factor for developing complications like acute myocardial infarction (AMI) and chronic heart failure. The mechanisms involved in cardiovascular aging are poorly understood, but microRNAs (miRNAs) are emerging as key biological regulators.

Results
We investigated the changes in mRNA and miRNA expression in hearts of aged mice (18 months old) compared to young mice (6 weeks old) by microarray profiling. Amongst the significantly upregulated miRNAs in aged hearts was the entire miR-34 family. MiR-34a is highly expressed and significantly correlates with age in human hearts as well (p=0.004). Inhibition of miR-34a in 18 month old mice using specific antagomirs against miR-34a (Ant-34a) reduced apoptosis in the heart (41.8±12.5%, P<0.05). Consistently, progeria-induced cardiac contractile dysfunction in KU80-/- mice was also ameliorated by miR-34a inhibition (Absolute ejection fraction (EF) increase: 17.7±2.1%). Moreover, 18 month old miR-34a-/- mice displayed superior cardiac contractile function (EF: 63.5±2.7%) and reduction in apoptosis and hypertrophy, compared to wt littermates (EF: 52.3±2.2%).
Furthermore, we found that AMI induces miR-34a in the heart and that silencing of miR-34a improves recovery after AMI. This is evidenced by an improvement in EF and wall motion score index (WMSI) 14 days after AMI in mice treated with Ant-34a (EF: Ant-Control: 19.9±2.3%, Ant-34a: 36.8±3.7%, p<0.05; WMSI: Ant-Control: 2.14±0.16, Ant-34a: 1.53±0.12, p<0.05), as well as a reduction in apoptosis and fibrosis (74.0±15.4% and 68±10.1% inhibition, p<0.05, resp.). One of the established targets of miR-34a is SIRT1, but AMI experiments with SIRT1+/- mice showed that the beneficial effects of miR-34a inhibition do not solely rely on SIRT1.
Next, we identified several novel potential targets of miR-34a, of which PNUTS (PPP1R10) is most strongly downregulated in aged hearts (89.4±4.2% inhibition, p<0.05). Regulation of PNUTS by miR-34a was confirmed in vitro and in vivo. PNUTS interacts with the telomere regulator TRF2 and overexpression of PNUTS abrogated miR-34a-dependent apoptosis and inhibited telomere erosion in cardiomyocytes, in a TRF2-dependent manner, as measured by the telomere erosion and DNA damage markers γH2AX and P-Chk2, as well as Q-FISH and Q-PCR telomere length analysis. Furthermore AAV9-mediated cardiac PNUTS overexpression abrogated AMI-induced contractile dysfunction (delta-WSMI: AAV-control: 0.31±0.14, AAV-PNUTS: 0.00±0.06)

Conclusion
Together, these results identify miR-34a as a key molecular regulator of cardiac function in aging and after AMI, through the attenuation of the telomere regulator PNUTS. Therapeutic inhibition of miR-34a constitutes a promising strategy to avert cardiac dysfunction during aging and after AMI.

References


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SessionTitle:

Basic and Translational Science Hot Line

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.