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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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    JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells [Basic Sciences] (2016)
    American Heart Association (AHA)
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    Publication Date: 2016-06-23
    Description: Objective— Jumonji C (JmjC) domain–containing proteins modify histone and nonhistone proteins thereby controlling cellular functions. However, the role of JmjC proteins in angiogenesis is largely unknown. Here, we characterize the expression of JmjC domain–containing proteins after inducing endothelial differentiation of murine embryonic stem cells and study the function of JmjC domain–only proteins in endothelial cell (EC) functions. Approach and Results— We identified a large number of JmjC domain–containing proteins regulated by endothelial differentiation of murine embryonic stem cells. Among the family of JmjC domain–only proteins, Jmjd8 was significantly upregulated on endothelial differentiation. Knockdown of Jmjd8 in ECs significantly decreased in vitro network formation and sprouting in the spheroid assay. JMJD8 is exclusively detectable in the cytoplasm, excluding a function as a histone-modifying enzyme. Mass spectrometry analysis revealed JMJD8-interacting proteins with known functions in cellular metabolism like pyruvate kinase M2. Accordingly, knockdown of pyruvate kinase M2 in human umbilical vein ECs decreased endothelial sprouting in the spheroid assay. Knockdown of JMJD8 caused a reduction of EC metabolism as measured by Seahorse Bioscience extracellular flux analysis. Conversely, overexpression of JMJD8 enhanced cellular oxygen consumption rate of ECs, reflecting an increased mitochondrial respiration. Conclusions— Jmjd8 is upregulated during endothelial differentiation and regulates endothelial sprouting and metabolism by interacting with pyruvate kinase M2.
    Keywords: Epigenetics, Gene Expression & Regulation, Vascular Disease
    Print ISSN: 1079-5642
    Electronic ISSN: 1524-4636
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 3
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    The Polarity Protein Scrib Is Essential for Directed Endothelial Cell Migration [Cellular Biology] (2013)
    American Heart Association (AHA)
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    Publication Date: 2013-03-15
    Description: Rationale: Polarity proteins are involved in the apico-basal orientation of epithelial cells, but relatively little is known regarding their function in mesenchymal cells. Objective: We hypothesized that polarity proteins also contribute to endothelial processes like angiogenesis. Methods and Results: Screening of endothelial cells revealed high expression of the polarity protein Scribble (Scrib). On fibronectin-coated carriers Scrib siRNA (siScrib) blocked directed but not random migration of human umbilical vein endothelial cells and led to an increased number and disturbed orientation of cellular lamellipodia. Coimmunoprecipitation/mass spectrometry and glutathione S-transferase (GST) pulldown assays identified integrin α5 as a novel Scrib interacting protein. By total internal reflection fluorescence (TIRF) microscopy, Scrib and integrin α5 colocalize at the basal plasma membrane of endothelial cells. Western blot and fluorescence activated cell sorting (FACS) analysis revealed that silencing of Scrib reduced the protein amount and surface expression of integrin α5 whereas surface expression of integrin αV was unaffected. Moreover, in contrast to fibronectin, the ligand of integrin α5, directional migration on collagen mediated by collagen-binding integrins was unaffected by siScrib. Mechanistically, Scrib supported integrin α5 recycling and protein stability by blocking its interaction with Rab7a, its translocation into lysosomes, and its subsequent degradation by pepstatin-sensitive proteases. In siScrib-treated cells, reinduction of the wild-type protein but not of PSD95, Dlg, ZO-1 (PDZ), or leucine rich repeat domain mutants restored integrin α5 abundance and directional cell migration. The downregulation of Scrib function in Tg(kdrl:EGFP) s843 transgenic zebrafish embryos delayed the angiogenesis of intersegmental vessels. Conclusions: Scrib is a novel regulator of integrin α5 turnover and sorting, which is required for oriented cell migration and sprouting angiogenesis.
    Keywords: Angiogenesis, Endothelium/vascular type/nitric oxide
    Print ISSN: 0009-7330
    Electronic ISSN: 1524-4571
    Topics: Medicine
    Published by American Heart Association (AHA)
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  • 4
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    Histone Deacetylase 9 Promotes Angiogenesis by Targeting the Antiangiogenic MicroRNA-17-92 Cluster in Endothelial Cells [Basic science] (2013)
    American Heart Association (AHA)
    Details
    Publication Date: 2013-02-14
    Description: Objective— Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear. Methods and Results— Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs. In vitro, silencing of HDAC9 reduces endothelial cell tube formation and sprouting. Furthermore, HDAC9 silencing decreases vessel formation in a spheroid-based Matrigel plug assay in mice and disturbs vascular patterning in zebrafish embryos. Genetic deletion of HDAC9 reduces retinal vessel outgrowth and impairs blood flow recovery after hindlimb ischemia. Consistently, overexpression of HDAC9 increases endothelial cell sprouting, whereas mutant constructs lacking the catalytic domain, the nuclear localization sequence, or sumoylation site show no effect. To determine the mechanism underlying the proangiogenic effect of HDAC9, we measured the expression of the microRNA (miR)-17–92 cluster, which is known for its antiangiogenic activity. We demonstrate that silencing of HDAC9 in endothelial cells increases the expression of miR-17–92. Inhibition of miR-17–20a rescues the sprouting defects induced by HDAC9 silencing in vitro and blocking miR-17 expression partially reverses the disturbed vascular patterning of HDAC9 knockdown in zebrafish embryos. Conclusion— We found that HDAC9 promotes angiogenesis and transcriptionally represses the miR-17–92 cluster.
    Keywords: Angiogenesis
    Print ISSN: 1079-5642
    Electronic ISSN: 1524-4636
    Topics: Medicine
    Published by American Heart Association (AHA)
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