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  • 1
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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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    Response to Hepatocyte Growth Factor and Cardiomyopathy in Dialysis Patients [Letters to the Editor] (2012)
    American Heart Association (AHA)
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    Publication Date: 2012-08-16
    Keywords: Angiogenesis, Myocardial cardiomyopathy disease, Peripheral vascular disease, Clinical Studies, Mechanism of atherosclerosis/growth factors
    Print ISSN: 0194-911X
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 3
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    Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction [Heart] (2016)
    American Heart Association (AHA)
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    Publication Date: 2016-01-14
    Description: We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin–positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other perisotin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.
    Keywords: Animal Models of Human Disease, Heart Failure
    Print ISSN: 0194-911X
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 4
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    Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow (2012)
    Oxford University Press
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    Publication Date: 2012-08-02
    Description: Aims We aimed to characterize the influence of acute myocardial infarction (AMI) on the metabolic activity of the bone marrow (BM) and on the composition and functional activity of BM-derived mononuclear cells (BMC). Acute ischaemia or other stressors induce the mobilization of progenitor cells from the BM stem cell niche. The effect of AMI on the numbers and functional activity of cells within the BM is unknown. Methods and results In patients of the REPAIR-AMI trial as well as in mice, the number and functionality of BMC was compared with respect to the time interval from AMI. Activation of Wnt signalling was assessed after AMI induction in TOP-GAL transgenic reporter mice, carrying a β-galactosidase gene driven by an LEF/TCF/β-catenin responsive promoter. The metabolic activity of the BM, as determined by F-18-fluorodeoxyglucose-positron emission tomography, was significantly higher in patients with AMI compared with patients with chronic post-ischaemic heart failure. Moreover, the number of haematopoietic CD34 + ( P 〈 0.05) and CD133 + ( P 〈 0.05) cells in the BM aspirates was significantly increased in patients within 7 days after AMI. In order to confirm these clinical data, we induced AMI in mice, which time-dependently increased the number of c-kit + Sca-1 + lin- cells and colony-forming units in the BM. Activation of the BM by AMI induced a significant increase in Wnt signalling, which is known to induce proliferation of haematopoietic stem cells, and demonstrated increased levels of the Wnt target Axin-2 in BM-derived cells on Day 7 ( P 〈 0.01 vs. control). Conclusion Acute myocardial infarction is associated with an increased metabolic activity and increased levels of progenitor cells within days after AMI. These findings document an activation of the stem cell niche within the BM following AMI, which may have important implications for the optimal timing of cell aspirations used for therapeutic application in patients with AMI.
    Print ISSN: 0195-668X
    Electronic ISSN: 1522-9645
    Topics: Medicine
    Published by Oxford University Press
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  • 5
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    Hepatocyte Growth Factor Inhibits Lipopolysaccharide-Induced Oxidative Stress via Epithelial Growth Factor Receptor Degradation [Cell Biology/Signaling] (2012)
    American Heart Association (AHA)
    Details
    Publication Date: 2012-10-19
    Description: Objective— Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II–induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism. Methods and Results— HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2–containing inositol 5'-phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model. Conclusion— The present study revealed inhibition of LPS-induced vascular cell adhesion molecule-1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2–containing inositol 5'-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease.
    Print ISSN: 1079-5642
    Electronic ISSN: 1524-4636
    Topics: Medicine
    Published by American Heart Association (AHA)
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