Dapagliflozin mitigates cellular stress and inflammation through PI3K/AKT pathway modulation in cardiomyocytes, aortic endothelial cells, and stem cell-derived β cells.
Glucosides
/ pharmacology
Proto-Oncogene Proteins c-akt
/ metabolism
Animals
Signal Transduction
/ drug effects
Myocytes, Cardiac
/ drug effects
Benzhydryl Compounds
/ pharmacology
Sodium-Glucose Transporter 2 Inhibitors
/ pharmacology
Endothelial Cells
/ drug effects
Inflammation Mediators
/ metabolism
Oxidative Stress
/ drug effects
Phosphatidylinositol 3-Kinase
/ metabolism
Anti-Inflammatory Agents
/ pharmacology
Cells, Cultured
Aorta
/ drug effects
Reactive Oxygen Species
/ metabolism
Cell Line
Cardiomegaly
/ pathology
AKT signaling
Beta cells
Cardiomyocyte
Dapagliflozin
Endothelial cells
Inflammation
Sodium-glucose cotransporter
Journal
Cardiovascular diabetology
ISSN: 1475-2840
Titre abrégé: Cardiovasc Diabetol
Pays: England
ID NLM: 101147637
Informations de publication
Date de publication:
29 Oct 2024
29 Oct 2024
Historique:
received:
28
07
2024
accepted:
21
10
2024
medline:
30
10
2024
pubmed:
30
10
2024
entrez:
30
10
2024
Statut:
epublish
Résumé
Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is well-recognized for its therapeutic benefits in type 2 diabetes (T2D) and cardiovascular diseases. In this comprehensive in vitro study, we investigated DAPA's effects on cardiomyocytes, aortic endothelial cells (AECs), and stem cell-derived beta cells (SC-β), focusing on its impact on hypertrophy, inflammation, and cellular stress. Our results demonstrate that DAPA effectively attenuates isoproterenol (ISO)-induced hypertrophy in cardiomyocytes, reducing cell size and improving cellular structure. Mechanistically, DAPA mitigates reactive oxygen species (ROS) production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation. Additionally, DAPA's modulation of SGLT2, the Na+/H + exchanger 1 (NHE1), and glucose transporter (GLUT 1) type 1 highlights its critical role in maintaining cellular ion balance and glucose metabolism, providing insights into its cardioprotective mechanisms. In aortic endothelial cells (AECs), DAPA exhibited notable anti-inflammatory properties by restoring AKT and phosphoinositide 3-kinase (PI3K) expression, enhancing mitogen-activated protein kinase (MAPK) activation, and downregulating inflammatory cytokines at both the gene and protein levels. Furthermore, DAPA alleviated tumor necrosis factor (TNFα)-induced inflammation and stress responses while enhancing endothelial nitric oxide synthase (eNOS) expression, suggesting its potential to preserve vascular function and improve endothelial health. Investigating SC-β cells, we found that DAPA enhances insulin functionality without altering cell identity, indicating potential benefits for diabetes management. DAPA also upregulated MAFA, PI3K, and NRF2 expression, positively influencing β-cell function and stress response. Additionally, it attenuated NLRP3 activation in inflammation and reduced NHE1 and glucose-regulated protein GRP78 expression, offering novel insights into its anti-inflammatory and stress-modulating effects. Overall, our findings elucidate the multifaceted therapeutic potential of DAPA across various cellular models, emphasizing its role in mitigating hypertrophy, inflammation, and cellular stress through the activation of the AKT pathway and other signaling cascades. These mechanisms may not only contribute to enhanced cardiac and endothelial function but also underscore DAPA's potential to address metabolic dysregulation in T2D. 1. DAPA effectively attenuates ISO-induced cardiomyocyte hypertrophy by reducing cell size and improving cellular structure. 2. DAPA exhibits anti-inflammatory properties in AECs by restoring AKT and PI3K expression, upregulating MAPK activation, and downregulating inflammatory gene expression. 3. DAPA enhances insulin functionality in SC-β cells without altering cell identity, suggesting potential benefits in diabetes management. 4. DAPA’s modulation of SGLT2, NHE1, and GLUT1 expression in cardiomyocytes underscores its role in cellular ion balance and glucose metabolism, contributing to its cardioprotective mechanisms. 5. DAPA alleviates TNFα-induced inflammation and stress responses in AECs, while enhancing eNOS expression, indicating its potential to preserve vascular function. 6. DAPA attenuates NLRP3 activation and reduces NHE1 and GRP78 expression in SC-β cells, offering novel insights into its anti-inflammatory and stress-modulating effects.
Autres résumés
Type: plain-language-summary
(eng)
1. DAPA effectively attenuates ISO-induced cardiomyocyte hypertrophy by reducing cell size and improving cellular structure. 2. DAPA exhibits anti-inflammatory properties in AECs by restoring AKT and PI3K expression, upregulating MAPK activation, and downregulating inflammatory gene expression. 3. DAPA enhances insulin functionality in SC-β cells without altering cell identity, suggesting potential benefits in diabetes management. 4. DAPA’s modulation of SGLT2, NHE1, and GLUT1 expression in cardiomyocytes underscores its role in cellular ion balance and glucose metabolism, contributing to its cardioprotective mechanisms. 5. DAPA alleviates TNFα-induced inflammation and stress responses in AECs, while enhancing eNOS expression, indicating its potential to preserve vascular function. 6. DAPA attenuates NLRP3 activation and reduces NHE1 and GRP78 expression in SC-β cells, offering novel insights into its anti-inflammatory and stress-modulating effects.
Identifiants
pubmed: 39472869
doi: 10.1186/s12933-024-02481-y
pii: 10.1186/s12933-024-02481-y
doi:
Substances chimiques
Glucosides
0
dapagliflozin
1ULL0QJ8UC
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Benzhydryl Compounds
0
Sodium-Glucose Transporter 2 Inhibitors
0
Inflammation Mediators
0
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Anti-Inflammatory Agents
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
388Subventions
Organisme : University of Sharjah
ID : 23010902135
Informations de copyright
© 2024. The Author(s).
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