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Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors

BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to inv...

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Autores principales: Scisciola, Lucia, Taktaz, Fatemeh, Fontanella, Rosaria Anna, Pesapane, Ada, Surina, Cataldo, Vittoria, Ghosh, Puja, Franzese, Martina, Puocci, Armando, Paolisso, Pasquale, Rafaniello, Concetta, Marfella, Raffaele, Rizzo, Maria Rosaria, Barbato, Emanuele, Vanderheyden, Marc, Barbieri, Michelangela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9896756/
https://www.ncbi.nlm.nih.gov/pubmed/36732760
http://dx.doi.org/10.1186/s12933-023-01754-2
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author Scisciola, Lucia
Taktaz, Fatemeh
Fontanella, Rosaria Anna
Pesapane, Ada
Surina
Cataldo, Vittoria
Ghosh, Puja
Franzese, Martina
Puocci, Armando
Paolisso, Pasquale
Rafaniello, Concetta
Marfella, Raffaele
Rizzo, Maria Rosaria
Barbato, Emanuele
Vanderheyden, Marc
Barbieri, Michelangela
author_facet Scisciola, Lucia
Taktaz, Fatemeh
Fontanella, Rosaria Anna
Pesapane, Ada
Surina
Cataldo, Vittoria
Ghosh, Puja
Franzese, Martina
Puocci, Armando
Paolisso, Pasquale
Rafaniello, Concetta
Marfella, Raffaele
Rizzo, Maria Rosaria
Barbato, Emanuele
Vanderheyden, Marc
Barbieri, Michelangela
author_sort Scisciola, Lucia
collection PubMed
description BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-01754-2
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spelling pubmed-98967562023-02-04 Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors Scisciola, Lucia Taktaz, Fatemeh Fontanella, Rosaria Anna Pesapane, Ada Surina Cataldo, Vittoria Ghosh, Puja Franzese, Martina Puocci, Armando Paolisso, Pasquale Rafaniello, Concetta Marfella, Raffaele Rizzo, Maria Rosaria Barbato, Emanuele Vanderheyden, Marc Barbieri, Michelangela Cardiovasc Diabetol Research BACKGROUND: Sodium-glucose co-transporters (SGLT) inhibitors (SGLT2i) showed many beneficial effects at the cardiovascular level. Several mechanisms of action have been identified. However, no data on their capability to act via epigenetic mechanisms were reported. Therefore, this study aimed to investigate the ability of SGLT2 inhibitors (SGLT2i) to induce protective effects at the cardiovascular level by acting on DNA methylation. METHODS: To better clarify this issue, the effects of empagliflozin (EMPA) on hyperglycemia-induced epigenetic modifications were evaluated in human ventricular cardiac myoblasts AC16 exposed to hyperglycemia for 7 days. Therefore, the effects of EMPA on DNA methylation of NF-κB, SOD2, and IL-6 genes in AC16 exposed to high glucose were analyzed by pyrosequencing-based methylation analysis. Modifications of gene expression and DNA methylation of NF-κB and SOD2 were confirmed in response to a transient SGLT2 gene silencing in the same cellular model. Moreover, chromatin immunoprecipitation followed by quantitative PCR was performed to evaluate the occupancy of TET2 across the investigated regions of NF-κB and SOD2 promoters. RESULTS: Seven days of high glucose treatment induced significant demethylation in the promoter regions of NF-kB and SOD2 with a consequent high level in mRNA expression of both genes. The observed DNA demethylation was mediated by increased TET2 expression and binding to the CpGs island in the promoter regions of analyzed genes. Indeed, EMPA prevented the HG-induced demethylation changes by reducing TET2 binding to the investigated promoter region and counteracted the altered gene expression. The transient SGLT2 gene silencing prevented the DNA demethylation observed in promoter regions, thus suggesting a role of SGLT2 as a potential target of the anti-inflammatory and antioxidant effect of EMPA in cardiomyocytes. CONCLUSIONS: In conclusion, our results demonstrated that EMPA, mainly acting on SGLT2, prevented DNA methylation changes induced by high glucose and provided evidence of a new mechanism by which SGLT2i can exert cardio-beneficial effects. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-023-01754-2 BioMed Central 2023-02-02 /pmc/articles/PMC9896756/ /pubmed/36732760 http://dx.doi.org/10.1186/s12933-023-01754-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Scisciola, Lucia
Taktaz, Fatemeh
Fontanella, Rosaria Anna
Pesapane, Ada
Surina
Cataldo, Vittoria
Ghosh, Puja
Franzese, Martina
Puocci, Armando
Paolisso, Pasquale
Rafaniello, Concetta
Marfella, Raffaele
Rizzo, Maria Rosaria
Barbato, Emanuele
Vanderheyden, Marc
Barbieri, Michelangela
Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title_full Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title_fullStr Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title_full_unstemmed Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title_short Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
title_sort targeting high glucose-induced epigenetic modifications at cardiac level: the role of sglt2 and sglt2 inhibitors
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9896756/
https://www.ncbi.nlm.nih.gov/pubmed/36732760
http://dx.doi.org/10.1186/s12933-023-01754-2
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