SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation

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...

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Vydáno v:	Scientific reports Ročník 14; číslo 1; s. 16459 - 15
Hlavní autoři:	Schmidt, Kevin, Schmidt, Arne, Groß, Sonja, Just, Annette, Pfanne, Angelika, Fuchs, Maximilian, Jordan, Maria, Mohr, Elisa, Pich, Andreas, Fiedler, Jan, Thum, Thomas
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 16.07.2024 Nature Publishing Group Nature Portfolio
Témata:	631/92/436 631/92/475 631/92/609 631/92/613 692/4017 692/4019 Actin Benzhydryl Compounds - pharmacology Cardiovascular diseases Cell migration Cell Movement - drug effects Cell proliferation Cell Proliferation - drug effects Congestive heart failure Cytoskeleton Electron transport Endothelial cell Endothelial cells Epithelial-Mesenchymal Transition - drug effects Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Fibrosis Glucose transporter Glucosides - pharmacology Heart diseases Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Humanities and Social Sciences Humans Inflammation Mode of action multidisciplinary Myocytes Na+/H+-exchanging ATPase Oxygen consumption Proteomics Science Science (multidisciplinary) siRNA Sodium Sodium-glucose transporter 2 inhibitors Sodium-Glucose Transporter 2 Inhibitors - pharmacology Sodium-Hydrogen Exchanger 1 - antagonists & inhibitors Sodium-Hydrogen Exchanger 1 - metabolism Umbilical vein Sodium-glucose transporter 2 inhibitors Endothelial cell Fibroblasts Oxygen consumption Inflammation Cardiovascular diseases Cell migration
ISSN:	2045-2322, 2045-2322
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-024-65410-9