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Open Access 01-12-2023 | Empagliflozin | Research

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

Authors: Lucia Scisciola, Fatemeh Taktaz, Rosaria Anna Fontanella, Ada Pesapane, Surina, Vittoria Cataldo, Puja Ghosh, Martina Franzese, Armando Puocci, Pasquale Paolisso, Concetta Rafaniello, Raffaele Marfella, Maria Rosaria Rizzo, Emanuele Barbato, Marc Vanderheyden, Michelangela Barbieri

Published in: Cardiovascular Diabetology | Issue 1/2023

Abstract

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

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Title: Targeting high glucose-induced epigenetic modifications at cardiac level: the role of SGLT2 and SGLT2 inhibitors
Authors: Lucia Scisciola
Fatemeh Taktaz
Rosaria Anna Fontanella
Ada Pesapane
Surina
Vittoria Cataldo
Puja Ghosh
Martina Franzese
Armando Puocci
Pasquale Paolisso
Concetta Rafaniello
Raffaele Marfella
Maria Rosaria Rizzo
Emanuele Barbato
Marc Vanderheyden
Michelangela Barbieri
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Empagliflozin
Hyperglycemia
Epigenetics
Published in: Cardiovascular Diabetology / Issue 1/2023
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-023-01754-2

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