Exogenous H2S protects H9c2 cardiac cells against high glucose-induced injury and inflammation by inhibiting the activation of the NF-κB and IL-1β pathways

Abstract

Abstract. Hyperglycemia has been reported to activate the nuclear factor-κB (NF-κB) pathway. We have previously demonstrated that exogenous hydrogen sulfide (H 2 S) protects cardiomyocytes against high glucose (HG)-induced injury by inhibiting the activity of p38 mitogen-activated protein kinase (MAPK), which can activate the NF-κB pathway and induce interleukin (IL)-1β production. In the present study, we aimed to investigate the hypothesis that exogenous H 2 S protects cardiomyocytes against HG-induced injury and inflammation through the inhibition of the NF-κB/IL-1β pathway. H9c2 cardiac cells were treated with 35 mM glucose (HG) for 24 h to establish a model of HG-induced damage. Our results demonstrated that treatment of the cells with 400 µM sodium hydrogen sulfide (NaHS, a donor of H 2 S) or 100 µM pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB) for 30 min prior to exposure to HG markedly attenuated the HG-induced increase in the expression levels of the phosphorylated (p)-NF-κB p65 subunit. Notably, pre-treatment of the H9c2 cardiac cells with NaHS or PDTC significantly suppressed the HG-induced injury, including cytotoxicity, apoptosis, oxidative stress and mitochondrial insults, as evidenced by an increase in cell viability, as well as a decrease in the number of apoptotic cells, the expression of cleaved caspase-3, the generation of reactive oxygen species (ROS) and the dissipation of mitochondrial membrane potential (MMP). In addition, pre-treatment of the cells with NaHS or PDTC ameliorated the HG-induced inflammatory response, leading to a decrease in the levels of IL-1β, IL-6 and tumor necrosis factor-α (TNF-α). Importantly, co-treatment of the H9c2 cells with 20 ng/ml IL-1 receptor antagonist (IL-1Ra) and HG markedly reduced the HG-induced increase in p-NF-κB p65 expression, cytoto xicity, the number of apoptotic cells, as well as the production of TNF-α. In conclusion, the present study presents novel mechanistic evidence that exogenous H 2 S protects H9c2 cardiac cells against HG-induced inflammation and injury, including cytotoxicity, apoptosis, overproduction of ROS and the dissipation of MMP, by inhibiting the NF-κB/IL-1β pathway. We also provide new data indicating that the positive interaction between the NF-κB pathway and IL-1β is critical in HG-induced injury and inflammation in H9c2 cardiac cells.

The Opening of ATP-Sensitive K+ Channels Protects H9c2 Cardiac Cells Against the High Glucose-Induced Injury and Inflammation by Inhibiting the ROS-TLR4-Necroptosis Pathway

“…In agreement with our recent studies [20, 21], after H9c2 cardiac cells were treated with HG for 24 h, the secretion levels of IL-1β (Fig. 8A) and TNF-α (Fig.…”

“…To date, multiple factors, such as ROS [7, 19-21], chronic inflammation [20, 22], cell death (including apoptosis and necroptosis) [7, 19-21], and activity of several signaling molecules, for example, toll-like receptors (TLRs) [22, 23], have been demonstrated to implicate in the hyperglycemia-induced cardiac injury. Importantly, the above factors can interact or crosstalk, consisting of the complicated intracellular signal mechanisms.…”

Role of Adipokines in Cardiovascular Disease

“…94, 95 Additionally, CTRP6 improves cardiac function and ameliorates ventricular remodeling post-MI, protecting against cardiac fibrosis by inhibiting myofibroblast differentiation, extracellular matrix production, and cardiac fibroblast migration via Smad-independent RhoA/MRTF-A (myocardin-related transcription factor-A) signaling ( Figure 5). 96 …”

GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes

“…Podocyte injury is involved in the progression of glomerulonephritis, DN, renal failure and other kidney diseases (40). Specifically, reductions in the number and density of podocytes have been linked to the pathological changes, which occur during DN (41). It has been suggested that podocyte phenotypic transformation, the process of its transdifferentiation into mesenchymal cells during cell damage, leads to the loss of specific podocyte protein markers, disrupted cell function and proteinuria (42).…”