Dapagliflozin Protects H9c2 Cells Against Injury Induced by Lipopolysaccharide via Suppression of CX3CL1/CX3CR1 Axis and NF-κB Activity

Abstract

Background: Dapagliflozin, a selective Sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been shown to play a key role in the control and management of the metabolic and cardiac disease. Objective: The current study aims to address the effects of dapagliflozin on the expression of fractalkine (FKN), known as CX3CL1, and its receptors CX3CR1, Nuclear factor-kappa B(NF-κB) p65 activity, Reactive oxygen species (ROS), and inflammation in LPS-treated H9c2 cell line. Methods: H9c2 cells were cultured with lipopolysaccharide (LPS) to establish a model of LPS-induced damage and then subsequently were treated with dapagliflozin for 72 h. Our work included measurement of cell viability (MTT), Malondialdehyde (MDA), intracellular ROS, tumor necrosis factor-α (TNF-α), NF-κB activity, and expression CX3CL1/CX3CR1. Results: The results showed that LPS-induced reduction of cell viability was successfully rescued by dapagliflozin treatment. The cellular levels of MDA, ROS, and TNF-α, as an indication of cellular oxidative stress and inflammation, were significantly elevated in H9c2 cells compared to the control group. Furthermore, dapagliflozin ameliorated inflammation and oxidative stress through the modulation of the levels of MDA, TNF-α, and ROS. Correspondingly, dapagliflozin reduced the expression of CX3CL1/CX3CR1, NF-κB p65 DNA binding activity and it also attenuated nuclear acetylated NF-κB p65 in LPS-induced injury in H9c2 cells compared to untreated cells. Conclusion: These findings shed light on the novel pharmacological potential of dapagliflozin in the alleviation of LPS-induced CX3CL1/CX3CR1-mediated injury in inflammatory conditions such as sepsis-induced cardiomyopathy.

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

“…Our data not only confirmed the effects of SGLT2i on NF-KB acetylation and phosphorylation previously demonstrated in kidney tissue, HUVEC, macrophages, and H9c2 [22,[43][44][45][46], but for the first time, evidence their ability to exert anti-inflammatory and antioxidant effect by modulating NF-kB and SOD2 DNA methylation, directly targeting cardiomyocyte SGLT2.…”

“…Furthermore, SGLT2i has been shown to also play an essential role in the reduction of oxidative stress, which is a primary contributor to the pathogenesis of the cardiovascular disease. Moreover, EMPA also affected the acetylation and phosphorylation status of NF-kB and SOD2, showing its capability to act at transcriptional and post-transduction levels [22,[43][44][45].…”

Narrative Review of Immunomodulatory and Anti-inflammatory Effects of Sodium-Glucose Cotransporter 2 Inhibitors: Unveiling Novel Therapeutic Frontiers

“…SGLT2 inhibitors have shown some evidence to exert their antiinflammatory effects via those signaling pathways in multiple in vivo and in vitro studies irrespective of glucose concentration. 39 , 40 , 41 , 42 , 43 An in vitro study using LPS-stimulated RAW 264.7 macrophages demonstrated that empagliflozin attenuated the release of proinflammatory cytokines and proinflammatory mediators such as nitric oxide or prostaglandin E2 via downregulating the NF-κB, mitogen-activated protein kinase, and Janus kinase/signal transducer and activator of transcription signaling pathways. 41 Another in vitro study involving human ventricular cardiac myoblasts revealed that empagliflozin mitigated the high glucose-induced DNA demethylation changes in NF-κB and superoxide dismutase 2 genes, and this finding was correlated with the decreased reactive oxygen species level and lower IL-6 gene expression.…”

Role and molecular mechanisms of SGLT2 inhibitors in pathological cardiac remodeling (Review)

“…Furthermore, DAPA Table II improves cardiac hypertrophy in streptozocin-induced type 2 diabetic rats by inhibiting the nuclear translocation of NF-κB and reducing the expression of calpain-1 in cardiomyocytes, decreasing IL-6 and TNF-α levels and upregulating IL-10 levels (58). In addition, DAPA regulates malondialdehyde, TNF-α and ROS levels by blocking the C-X3-C motif chemokine ligand 1/receptor 1 axis and NF-κB activity, thereby reducing lipopolysaccharide-induced inflammation and oxidative stress (121). However, this study was performed in vitro using H9C2 cells and requires validation in patients.…”