SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation.

Humans Sodium-Glucose Transporter 2 Inhibitors / pharmacology Human Umbilical Vein Endothelial Cells / drug effects Benzhydryl Compounds / pharmacology Glucosides / pharmacology Fibroblasts / drug effects Epithelial-Mesenchymal Transition / drug effects Sodium-Hydrogen Exchanger 1 / metabolism Cell Movement / drug effects Cell Proliferation / drug effects
Cardiovascular diseases Cell migration Endothelial cell Fibroblasts Inflammation Oxygen consumption Sodium-glucose transporter 2 inhibitors

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
16 Jul 2024
Historique:
received: 09 02 2024
accepted: 19 06 2024
medline: 17 7 2024
pubmed: 17 7 2024
entrez: 16 7 2024
Statut: epublish

Résumé

Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells. Proteomic analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performed in vitro EndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs.

Identifiants

DOI: 10.1038/s41598-024-65410-9 PMID: 39013942
pubmed: 39013942
doi: 10.1038/s41598-024-65410-9
pii: 10.1038/s41598-024-65410-9
doi:

Substances chimiques

Sodium-Glucose Transporter 2 Inhibitors 0
Benzhydryl Compounds 0
Glucosides 0
empagliflozin HDC1R2M35U
dapagliflozin 1ULL0QJ8UC
Sodium-Hydrogen Exchanger 1 0
SLC9A1 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

16459

Subventions

Organisme : Deutsche Forschungsgemeinschaft
ID : 437531118

Informations de copyright

© 2024. The Author(s).

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Auteurs

Kevin Schmidt (K)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.

Arne Schmidt (A)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.

Sonja Groß (S)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Annette Just (A)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Angelika Pfanne (A)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Maximilian Fuchs (M)

Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.

Maria Jordan (M)

Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.

Elisa Mohr (E)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Andreas Pich (A)

Institute of Toxicology and Core Unit Proteomics, Hannover Medical School, Hannover, Germany.

Jan Fiedler (J)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany. Jan.Fiedler@item.fraunhofer.de.
Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany. Jan.Fiedler@item.fraunhofer.de.
Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany. Jan.Fiedler@item.fraunhofer.de.

Thomas Thum (T)

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany. Thum.Thomas@mh-hannover.de.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › Inhibiteurs du cotransporteur sodium-glucose de type 2 › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › Cellules endothéliales de la veine ombilicale humaine › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Composés benzhydryliques › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Glucides › Hétérosides › Glucosides › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Fibroblastes › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transdifférenciation cellulaire › Transition épithélio-mésenchymateuse › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Antiport des ions sodium-hydrogène › Échangeur-1 de sodium-hydrogène › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Phénomènes physiologiques › Mouvement cellulaire › SGLT2 inhibitors attenuate endothelial to...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › SGLT2 inhibitors attenuate endothelial to...