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    MicroRNA-34a regulates cardiac ageing and function (2013)
    Nature Publishing Group (NPG)
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    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
    Published by Nature Publishing Group (NPG)
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  • 2
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    Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury (2014)
    Oxford University Press
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    Publication Date: 2014-08-28
    Description: Aims MicroRNA (miR)-92a is an important regulator of endothelial proliferation and angiogenesis after ischaemia, but the effects of miR-92a on re-endothelialization and neointimal lesion formation after vascular injury remain elusive. We tested the effects of lowering miR-92a levels using specific locked nucleic acid (LNA)-based antimiRs as well as endothelial-specific knock out of miR-92a on re-endothelialization and neointimal formation after wire-induced injury of the femoral artery in mice. Methods and results MiR-92a was significantly up-regulated in neointimal lesions following wire-induced injury. Pre-miR-92a overexpression resulted in repression of the direct miR-92a target genes integrin α5 and sirtuin1, and reduced eNOS expression in vitro . MiR-92a impaired proliferation and migration of endothelial cells but not smooth muscle cells. In vivo , systemic inhibition of miR-92a expression with LNA-modified antisense molecules resulted in a significant acceleration of re-endothelialization of the denuded vessel area. Genetic deletion of miR-92a in Tie2-expressing cells, representing mainly endothelial cells, enhanced re-endothelialization, whereas no phenotype was observed in mice lacking miR-92a expression in haematopoietic cells. The enhanced endothelial recovery was associated with reduced accumulation of leucocytes and inhibition of neointimal formation 21 days after injury and led to the de-repression of the miR-92a targets integrin α5 and sirtuin1. Conclusion Our data indicate that inhibition of endothelial miR-92a attenuates neointimal lesion formation by accelerating re-endothelialization and thus represents a putative novel mechanism to enhance the functional recovery following vascular injury.
    Print ISSN: 0008-6363
    Electronic ISSN: 1755-3245
    Topics: Medicine
    Published by Oxford University Press
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