Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis
Clinical use of doxorubicin (Dox), an anthracycline with potent anti-tumor effects, is limited because of its highly chemotherapy-induced cardiotoxicity (CIC). After myocardial infarction (MI), we have recently identified Yin Yang-1 (YY1) and histone deacetylase 4 (HDAC4) as two factors involved in...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253123001178 |
| _version_ | 1797823155505463296 |
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| author | Antonio Lax Fernando Soler Maria Josefa Fernandez del Palacio Silvia Pascual-Oliver Miriam Ruiz Ballester Jose Javier Fuster Domingo Pascual-Figal Maria del Carmen Asensio-Lopez |
| author_facet | Antonio Lax Fernando Soler Maria Josefa Fernandez del Palacio Silvia Pascual-Oliver Miriam Ruiz Ballester Jose Javier Fuster Domingo Pascual-Figal Maria del Carmen Asensio-Lopez |
| author_sort | Antonio Lax |
| collection | DOAJ |
| description | Clinical use of doxorubicin (Dox), an anthracycline with potent anti-tumor effects, is limited because of its highly chemotherapy-induced cardiotoxicity (CIC). After myocardial infarction (MI), we have recently identified Yin Yang-1 (YY1) and histone deacetylase 4 (HDAC4) as two factors involved in the overexpression of the isoform soluble suppression of tumorigenicity 2 (sST2) protein, which acts as a decoy receptor blocking the favorable effects of IL-33. Therefore, high levels of sST2 are associated with increased fibrosis, remodeling, and worse cardiovascular outcomes. No data exist on the role of the YY1/HDAC4/sST2 axis in CIC. This study aimed to evaluate the pathophysiological implication of the molecular YY1/HDAC4/sST2 axis in remodeling that is developed in patients treated with Dox as well as to suggest a novel molecular therapy to prevent anthracycline-induced cardiotoxicity. Here, we have characterized a novel nexus between miR106b-5p (miR-106b) levels and the YY1/HDAC4 axis in relation to the cardiac expression of sST2 using two experimental models with Dox-induced cardiotoxicity. The addition of Dox (5 μM) to human induced pluripotent stem cell-derived cardiomyocytes induced cellular apoptotic death via upregulation of miR-106b-5p (miR-106b), which was confirmed by specific mimic sequences. A functional blockage of miR-106b using the locked nucleic acid antagomir inhibited Dox-induced cardiotoxicity. |
| first_indexed | 2024-03-13T10:18:53Z |
| format | Article |
| id | doaj.art-7f5ddf751718429e8e8d49fae8e7e802 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-03-13T10:18:53Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-7f5ddf751718429e8e8d49fae8e7e8022023-05-21T04:34:49ZengElsevierMolecular Therapy: Nucleic Acids2162-25312023-06-0132704720Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axisAntonio Lax0Fernando Soler1Maria Josefa Fernandez del Palacio2Silvia Pascual-Oliver3Miriam Ruiz Ballester4Jose Javier Fuster5Domingo Pascual-Figal6Maria del Carmen Asensio-Lopez7Biomedical Research Institute Virgen de la Arrixaca (IMIB-Arrixaca), University of Murcia, 30120 Murcia, Spain; Corresponding author: Antonio Lax, University of Murcia, Ctra. Madrid-Cartagena s/n, 30120 Murcia, Spain.Biomedical Research Institute Virgen de la Arrixaca (IMIB-Arrixaca), University of Murcia, 30120 Murcia, SpainVeterinary Hospital, University of Murcia 30100 Murcia, SpainBiomedical Research Institute Virgen de la Arrixaca (IMIB-Arrixaca), University of Murcia, 30120 Murcia, SpainBiomedical Research Institute Virgen de la Arrixaca (IMIB-Arrixaca), University of Murcia, 30120 Murcia, SpainCentro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, 30120 Murcia, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, SpainCentro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; Corresponding author: Maria del Carmen Asensio-López, Hematovascular Pathophysiology, Spanish National Center for Cardiovascular Research (CNIC), Madrid, Spain.Clinical use of doxorubicin (Dox), an anthracycline with potent anti-tumor effects, is limited because of its highly chemotherapy-induced cardiotoxicity (CIC). After myocardial infarction (MI), we have recently identified Yin Yang-1 (YY1) and histone deacetylase 4 (HDAC4) as two factors involved in the overexpression of the isoform soluble suppression of tumorigenicity 2 (sST2) protein, which acts as a decoy receptor blocking the favorable effects of IL-33. Therefore, high levels of sST2 are associated with increased fibrosis, remodeling, and worse cardiovascular outcomes. No data exist on the role of the YY1/HDAC4/sST2 axis in CIC. This study aimed to evaluate the pathophysiological implication of the molecular YY1/HDAC4/sST2 axis in remodeling that is developed in patients treated with Dox as well as to suggest a novel molecular therapy to prevent anthracycline-induced cardiotoxicity. Here, we have characterized a novel nexus between miR106b-5p (miR-106b) levels and the YY1/HDAC4 axis in relation to the cardiac expression of sST2 using two experimental models with Dox-induced cardiotoxicity. The addition of Dox (5 μM) to human induced pluripotent stem cell-derived cardiomyocytes induced cellular apoptotic death via upregulation of miR-106b-5p (miR-106b), which was confirmed by specific mimic sequences. A functional blockage of miR-106b using the locked nucleic acid antagomir inhibited Dox-induced cardiotoxicity.http://www.sciencedirect.com/science/article/pii/S2162253123001178MT: Oligonucleotides: Therapies and ApplicationsmiR106banthracyclinecardiotoxicityheart failuresoluble ST2 isoform |
| spellingShingle | Antonio Lax Fernando Soler Maria Josefa Fernandez del Palacio Silvia Pascual-Oliver Miriam Ruiz Ballester Jose Javier Fuster Domingo Pascual-Figal Maria del Carmen Asensio-Lopez Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications miR106b anthracycline cardiotoxicity heart failure soluble ST2 isoform |
| title | Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis |
| title_full | Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis |
| title_fullStr | Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis |
| title_full_unstemmed | Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis |
| title_short | Silencing of microRNA-106b-5p prevents doxorubicin-mediated cardiotoxicity through modulation of the PR55α/YY1/sST2 signaling axis |
| title_sort | silencing of microrna 106b 5p prevents doxorubicin mediated cardiotoxicity through modulation of the pr55α yy1 sst2 signaling axis |
| topic | MT: Oligonucleotides: Therapies and Applications miR106b anthracycline cardiotoxicity heart failure soluble ST2 isoform |
| url | http://www.sciencedirect.com/science/article/pii/S2162253123001178 |
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