The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin.
Animals
Anti-Inflammatory Agents
/ pharmacology
Antifibrotic Agents
/ pharmacology
Apoptosis
/ drug effects
Benzhydryl Compounds
/ pharmacology
Cardiotoxicity
Cell Line
Cytokines
/ metabolism
Disease Models, Animal
Doxorubicin
Female
Ferroptosis
/ drug effects
Fibrosis
Glucosides
/ pharmacology
Heart Diseases
/ chemically induced
Inflammasomes
/ metabolism
Inflammation Mediators
/ metabolism
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
/ metabolism
Myocytes, Cardiac
/ drug effects
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Signal Transduction
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Ventricular Function, Left
/ drug effects
Cardio-Oncology
Doxorubicin
EMPA
Inflammation
Interleukins
Journal
Cardiovascular diabetology
ISSN: 1475-2840
Titre abrégé: Cardiovasc Diabetol
Pays: England
ID NLM: 101147637
Informations de publication
Date de publication:
23 07 2021
23 07 2021
Historique:
received:
15
02
2021
accepted:
16
07
2021
entrez:
24
7
2021
pubmed:
25
7
2021
medline:
4
1
2022
Statut:
epublish
Résumé
Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA-REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of EMPA in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analysed. We aimed to evaluate the effects of EMPA on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and MyD88-related pathways resulting in anti-apoptotic and anti-fibrotic effects. Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to EMPA. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca Cardiomyocytes exposed to doxorubicin increased the intracellular Ca EMPA reduced ferroptosis, fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in significant improvements in cardiac functions. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.
Sections du résumé
BACKGROUND
Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA-REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of EMPA in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analysed. We aimed to evaluate the effects of EMPA on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and MyD88-related pathways resulting in anti-apoptotic and anti-fibrotic effects.
METHODS
Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to EMPA. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca
RESULTS
Cardiomyocytes exposed to doxorubicin increased the intracellular Ca
CONCLUSION
EMPA reduced ferroptosis, fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in significant improvements in cardiac functions. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.
Identifiants
pubmed: 34301253
doi: 10.1186/s12933-021-01346-y
pii: 10.1186/s12933-021-01346-y
pmc: PMC8305868
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Antifibrotic Agents
0
Benzhydryl Compounds
0
Cytokines
0
Glucosides
0
Inflammasomes
0
Inflammation Mediators
0
Myd88 protein, mouse
0
Myeloid Differentiation Factor 88
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nlrp3 protein, mouse
0
Sodium-Glucose Transporter 2 Inhibitors
0
Doxorubicin
80168379AG
empagliflozin
HDC1R2M35U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
150Informations de copyright
© 2021. The Author(s).
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