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      Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity

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          Abstract

          Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeutic modulation of microRNA expression is emerging as a cardioprotective approach in several cardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclines and is involved in cardiac repair. In our previous study, we demonstrated beneficial effects of miR-34a silencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluate the potential cardioprotective properties of a specific antimiR-34a (Ant34a) in an experimental model of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administration of Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXO-induced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients.

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          Cardiac Fibrosis: The Fibroblast Awakens.

          Joshua G Travers, Fadia Kamal, Jeffrey Robbins … (2016)
          Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
          Article 0 comments Cited 561 times – based on 0 reviews     Review now
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            Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders.

            Anu Kauppinen, Tiina Suuronen, Johanna Ojala … (2013)
            Recent studies have indicated that the regulation of innate immunity and energy metabolism are connected together through an antagonistic crosstalk between NF-κB and SIRT1 signaling pathways. NF-κB signaling has a major role in innate immunity defense while SIRT1 regulates the oxidative respiration and cellular survival. However, NF-κB signaling can stimulate glycolytic energy flux during acute inflammation, whereas SIRT1 activation inhibits NF-κB signaling and enhances oxidative metabolism and the resolution of inflammation. SIRT1 inhibits NF-κB signaling directly by deacetylating the p65 subunit of NF-κB complex. SIRT1 stimulates oxidative energy production via the activation of AMPK, PPARα and PGC-1α and simultaneously, these factors inhibit NF-κB signaling and suppress inflammation. On the other hand, NF-κB signaling down-regulates SIRT1 activity through the expression of miR-34a, IFNγ, and reactive oxygen species. The inhibition of SIRT1 disrupts oxidative energy metabolism and stimulates the NF-κB-induced inflammatory responses present in many chronic metabolic and age-related diseases. We will examine the molecular mechanisms of the antagonistic signaling between NF-κB and SIRT1 and describe how this crosstalk controls inflammatory process and energy metabolism. In addition, we will discuss how disturbances in this signaling crosstalk induce the appearance of chronic inflammation in metabolic diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
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              MicroRNA-34a regulates cardiac ageing and function.

              Reinier A Boon, Kazuma Iekushi, Stefanie Lechner … (2013)
              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.
              Article 0 comments Cited 290 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Elena Piegari: elena.piegari@unicampania.it
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 23 July 2020
                Publication date PMC-release: 23 July 2020
                Publication date Collection: 2020
                Volume: 10
                Electronic Location Identifier: 12250
                Affiliations
                [1 ]ISNI 0000 0001 2200 8888, GRID grid.9841.4, Department of Experimental Medicine, Section of Pharmacology, , University of Campania “Luigi Vanvitelli”, ; Via Costantinopoli 16, 80138 Naples, Italy
                [2 ]ISNI 0000 0001 2168 2547, GRID grid.411489.1, Department of Experimental and Clinical Medicine, , University “Magna Graecia” of Catanzaro, ; Viale Europa, 88100 Catanzaro, Italy
                Article
                Publisher ID: 69038
                DOI: 10.1038/s41598-020-69038-3
                PMC ID: 7378226
                PubMed ID: 32704131
                SO-VID: af623919-87e0-4d08-8fd7-d34039922ba5
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 28 November 2019
                Date accepted : 7 July 2020
                Funding
                Funded by: Regione Campania L.R.n.5/2002 “Nuove strategie terapeutiche per ridurre o prevenire la cardiotossicità della doxorubicina” to E.P., “Cardiotossicità da Doxorubicina: meccanismi fisiopatologici, indici precoci di danno miocardico e terapie innovative” to L.B. and by the MIUR Projects PON03PE_00060_7 and PON03PE_00060_8
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Uncategorized
                Keywords: pharmacology,mirnas,cardiovascular diseases
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: pharmacology, mirnas, cardiovascular diseases

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