Endotoxin stress-response in cardiomyocytes: NF-κB activation and tumor necrosis factor-α expression

Wright, Gary; Singh, Ishwar; Hasday, Jeffery D.; Farrance, Iain K.; Hall, Gentzon; Cross, A. S.; Rogers, Terry B.

doi:10.1152/ajpheart.00256.2001

Cited by 78 publications

(54 citation statements)

References 38 publications

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“…Over production of TNF-α and LPS stimulation may induce the activity of NF-κB and exert harmful effects on myocardial cells (35). The current results revealed that sitagliptin is able to reduce LPS-induced TNF-α production and inhibit the nuclear translocation of NF-κB.…”

Section: A B Cmentioning

confidence: 53%

Sitagliptin attenuates inﬂammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

Lin¹,

Lin²

2016

Experimental and Therapeutic Medicine

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Abstract. Glucagon-like peptide-1 (GLP-1) and GLP-1 receptors (GLP-1Rs) are responsible for glucose homeostasis, and have been shown to reduce inflammation in preclinical studies. The aim of the present study was to determine whether sitagliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), as a GLP-1 receptor agonist, exerts an anti-inflammatory effect on cardiomyoblasts during lipopolysaccharide (LPS) stimulation. Exposure to LPS increased the expression levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL)-6 and IL-1β in H9c2 cells, and also resulted in elevations in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression and nuclear factor-κB (NF-κB) nuclear translocation. Treatment with the DPP-4 inhibitor sitagliptin dose-dependently downregulated the mRNA levels of IL-6, COX-2 and iNOS in LPS-stimulated H9c2 cells. In addition, sitagliptin inhibited the increased protein expression of IL-6, TNF-α and IL-1β. NF-κB mRNA expression was reduced and its translocation to the nucleus was suppressed by treatment with sitagliptin. The present results demonstrated that sitagliptin exerts a beneficial effect on cardiomyoblasts exposed to LPS by inhibiting expression of inflammatory mediators and suppressing NF-κB activation. These findings indicate that the DPP-4 inhibitor sitagliptin may serve a function in cardiac remodeling attributed to sepsis-induced inflammation.

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Section: A B Cmentioning

confidence: 53%

Sitagliptin attenuates inﬂammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

Lin¹,

Lin²

2016

Experimental and Therapeutic Medicine

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“…The exact mechanisms of this LPS-induced IL-6 production in myocytes remain to be defined, although there are several possible pathways that have already been proposed. These include activation of signalling pathways through activation of the Toll-like receptors (Gallaci et al, 1998) and production of NF-κB transcriptional factor (Wright et al, 2002) and reactive oxygen species (Shang et al, 2006), all of which can increase the production and secretion of IL-6 and other cytokines like TNF-α.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin modulates constitutive and lipopolysaccharide induced IL-6 secretion in precursors of human skeletal muscle

Golicnik¹,

Podbregar²,

Lainščak³

et al. 2012

Afr. J. Pharm. Pharmacol.

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It is well documented that, besides reducing blood LDL lipoproteins, HMG-CoA reductase inhibitors (statins) also suppress inflammatory markers and improve survival in sepsis. These beneficial effects can be at least partly explained by their capacity to inhibit the release of IL-6, which is generally regarded as a proinflammatory cytokine, although a variety of other actions including anti-inflammatory have been reported for this cytokine under various circumstances. In quantitative terms, IL-6 release is a major response of the skeletal muscle to various environmental stimuli and since muscle represents 40% of the body weight it can substantially contribute to the IL-6 blood level. The aim of our study was to provide more detailed insight into the effects of statins on the IL-6 release from the human skeletal muscle. Studying time and concentration dependency of the constitutive and lipopolysaccharide (LPS)-stimulated IL-6 release from the cultured human myotubes we found that 48 h pre-treatment with atorvastatin (AT) significantly inhibits constitutive IL-6 secretion at high (1 μM) and supra (10 μM and 100 μM) therapeutic concentrations. At these AT concentrations, LPS-stimulated IL-6 secretion was also significantly reduced by 48 h AT co-treatment or pre-treatment, but not by post-treatment; therapeutic (0.1 μM) AT concentration was efficient only in pre-treatment but not in co-treatment or post-treatment LPS protocols. This information is an important clue for the investigations of the molecular mechanisms underlying AT effects and its therapeutic applications.

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“…Myocyte Cultures-Primary neonatal cardiomyocytes were isolated from 1-to 2-day-old CD-1 mouse pups using a previously described (14) method that produces cultures that exhibit spontaneous beating and Ͼ95% myocyte purity. Cells were plated on gelatin-coated plates at a density of 2 ϫ 10 6 cells per 60 mm diameter culture dish, in DMEM/F12 medium supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Activation of the Prolyl Hydroxylase Oxygen-sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes

Wright

Higgin

Raines

et al. 2003

Journal of Biological Chemistry

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Recently an oxygen-sensing/transducing mechanism has been identified as a family of O 2 -dependent prolyl hydroxylase domain-containing enzymes (PHD). In normoxia, PHD hydroxylates a specific proline residue that directs the degradation of constitutively synthesized hypoxia-inducible factor-1␣. During hypoxia, the cessation of hydroxylation of this proline results in less degradation and thus increases hypoxia-inducible factor-1␣ protein levels. In this study we have examined the consequences of activating the PHD oxygen-sensing pathway in cultured neonatal myocytes using ethyl-3,4 dihydroxybenzoate and dimethyloxalylglycine, inhibitors that, similar to hypoxia, inhibit this family of O 2 -dependent PHD enzymes. Increased glucose uptake and enhanced glycolytic metabolism are classical cellular responses to hypoxia. Ethyl-3,4 dihydroxybenzoate treatment of cardiomyocyte cultures for 24 h increased [ 3 H]deoxy-4-glucose uptake concurrent with an induction of GLUT1 protein. In addition, ethyl-3,4 dihydroxybenzoate, dimethyloxalylglycine, and hypoxia treatments were found to induce protein levels of nitricoxide synthase-2 and heme oxygenase-1, two important cardioregulatory proteins whose expression in response to hypoxic conditions is poorly understood. In conjunction with these changes in gene expression, activation of the PHD oxygen-sensing mechanism was found to preserve myocyte viability in the face of metabolic inhibition with cyanide and 2-deoxyglucose. These results point to a key role for the PHD pathway in the phenotypic changes that are observed in a hypoxic myocyte and may suggest a strategy to pharmacologically induce protection in heart.

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Endotoxin stress-response in cardiomyocytes: NF-κB activation and tumor necrosis factor-α expression

Cited by 78 publications

References 38 publications

Sitagliptin attenuates inﬂammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

Sitagliptin attenuates inﬂammatory responses in lipopolysaccharide-stimulated cardiomyocytes via nuclear factor-κB pathway inhibition

Atorvastatin modulates constitutive and lipopolysaccharide induced IL-6 secretion in precursors of human skeletal muscle

Activation of the Prolyl Hydroxylase Oxygen-sensor Results in Induction of GLUT1, Heme Oxygenase-1, and Nitric-oxide Synthase Proteins and Confers Protection from Metabolic Inhibition to Cardiomyocytes

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