Myocardial Tumor Necrosis Factor-alpha Research Articles

Effects of isoflurane preconditioning in the delayed phase on myocardial tumor necrosis factor alpha levels and caspase-3 protein expression in a rabbit model of ischemia-reperfusion injury.

This study aimed to investigate the protective effects and the mechanisms underlying these effects of isoflurane preconditioning in the delayed phase of myocardial ischemia-reperfusion injury. We randomly divided 30 healthy male New Zealand white rabbits into three groups with 10 rabbits in each group as follows: sham operation group (C group), ischemia-reperfusion group (I/R group), and 2.0% isoflurane preconditioning group (S group). Rabbits in the C group received thoracotomy for 160 min. Rabbits in the I/R group underwent left coronary artery occlusion for 40 min and reperfusion for 120 min. Rabbits in the S group received inhalation of 2.0% isoflurane and 100% oxygen for 2 h; after 24 h, rabbits in this group received the same treatment as that administered to rabbits in the I/R group. We examined the tumor necrosis factor alpha (TNF-α) levels in each group 20 min before occlusion of the left coronary, 20 and 40 min after occlusion of the left coronary artery, and 1 and 2 h after myocardial reperfusion. After reperfusion, immunoblotting was used to measure the myocardial caspase-3 expression levels, and the infarct size was measured using Evans blue and tetrazolium chloride staining. The levels of TNF-α and caspase-3 were lower in the S group than in the I/R group, and the myocardial infarct size decreased in the S group. Thus, isoflurane preconditioning in the delayed phase exerted protective effects by decreasing the myocardial caspase-3 expression and TNF-α production in a rabbit model of ischemia-reperfusion injury.

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that causes cardiac dysfunction during sepsis. Na/K-ATPase regulates intracellular Ca(2+), which activates mammalian target of rapamycin (mTOR), a regulator of protein synthesis. The aim of this study was to investigate the role of Na/K-ATPase/mTOR signaling in myocardial TNF-α expression during endotoxemia. Results showed that treatment with LPS decreased Na/K-ATPase activity in the myocardium in vivo and in cultured neonatal cardiomyocytes. Inhibition of Na/K-ATPase by ouabain enhanced LPS-induced myocardial TNF-α protein production, but had no effect on TNF-α mRNA expression. More importantly, ouabain further decreased in vivo cardiac function in endotoxemic mice, which was blocked by etanercept, a TNF-α antagonist. LPS-induced reduction in Na/K-ATPase activity was prevented by inhibition of PI3K, Rac1 and NADPH oxidase using LY294002, a dominant-negative Rac1 adenovirus (Ad-Rac1N17) and apocynin, respectively. To assess the role of Rac1 in Ca(2+) handling, Ca(2+) transients in adult cardiomyocytes from cardiomyocyte-specific Rac1 knockout (Rac1(CKO)) and wild-type (WT) mice were determined. LPS increased intracellular Ca(2+) in WT but not in Rac1(CKO) cardiomyocytes. Furthermore, LPS rapidly increased mTOR phosphorylation in cardiomyocytes, which was blocked by Rac1N17 and an inhibitor of calmodulin-dependent protein kinases (CaMKs) KN93, but enhanced by ouabain. Rapamycin, an inhibitor of mTOR suppressed TNF-α protein levels without any significant effect on its mRNA expression or global protein synthesis. In conclusion, myocardial Na/K-ATPase activity is inhibited during endotoxemia via PI3K/Rac1/NADPH oxidase activation. Inhibition of Na/K-ATPase activates Ca(2+)/CaMK/mTOR signaling, which promotes myocardial TNF-α protein production and cardiac dysfunction during endotoxemia.

Insulin-Mediated Inhibition of p38 Mitogen-Activated Protein Kinase Protects Cardiomyocytes in Severe Burns

Thermal injury inhibits Akt activation and upregulates p38 mitogen-activated protein kinase, which in turn induces inflammation and increases apoptosis. This study aimed to elucidate the mechanism underlying the cytoprotective role of insulin in severe burns by examining the effects of insulin on inflammation and apoptosis mediated by p38 mitogen-activated protein kinase in burn serum-challenged cardiomyocytes. Neonatal rat cardiomyocytes were exposed to burn serum for 6 hours in the presence or absence of insulin and pretreated with inhibitors to p38 mitogen-activated protein kinase (SB203580) and Akt (LY294002). The authors examined expression of myocardial tumor necrosis factor-alpha, cardiac myofilament proteins caspase-3 and Bcl2, and apoptosis. Burn serum-induced upregulation of tumor necrosis factor was inhibited by both SB203580 and insulin. LY294002 reversed insulin-mediated downregulation of tumor necrosis factor. Both SB203580 and insulin inhibited apoptosis, resulting in fewer pyknotic nuclei and inhibition of caspase-3 activation and Bcl2 downregulation. LY294002 reversed insulin-mediated inhibition of apoptosis. Insulin decreases inflammatory cytokine expression and apoptosis via PI3K/Akt-mediated inhibition of p38 mitogen-activated protein kinase. The cytoprotective role of insulin suggests that it may have a potential role in strategies for treating thermal injuries.

Myocardial tumor necrosis factor-alpha expression in a sudden death due to dilated cardiomyopathy with endomyoelastofibrosis

During the clinical course of dilated cardiomyopathy, arrhythmias, thromboembolism and sudden death are common and may occur at any stage. In patients with dilated cardiomyopathy, elevated plasma levels of tumor necrosis factor-α are associated with poor prognosis. In animal experiments and clinical trials, myocardial tumor necrosis factor-α expression correlates with increased mortality rates. A case of sudden death of a previously asymptomatic young man, having a definitive autoptic diagnosis of dilated cardiomyopathy with endomyoelastofibrosis, is presented. We investigated the cardiac morphology and the expression of tumor necrosis factor-α in cardiac tissue specimens to elucidate the role of tumor necrosis factor-α expression in this fatal case. Our results demonstrate a strong positive myocytes reaction for tumor necrosis factor-α in the heart specimens. The pathogenesis of the fatal event is discussed with particular reference to the histological findings and myocytes expression of tumor necrosis factor-α.

Cellular and Hemodynamics Responses of Failing Myocardium to Continuous Flow Mechanical Circulatory Support Using the DeBakey-Noon Left Ventricular Assist Device: a Comparative Analysis With Pulsatile-Type Devices

An increasing number of continuous flow pumps are currently under clinical studies, however very little data exist on the hemodynamic and cellular responses of the failing heart to continuous flow support. The purpose of this investigation was to characterize the response of the failing myocardium to continuous flow support. We compared echocardiographic and cellular markers of failing myocardium at the time of left ventricular assist device (LVAD) implantation and explantation in 20 consecutive patients (12 pulsatile flow [Novacor] and 8 continuous flow [DeBakey-Noon]). The use of mechanical support with both continuous- or pulsatile-type LVADs resulted in a reduction of left ventricular end-diastolic dimension (LVEDD), end-diastolic volume (EDV), end-systolic volume (ESV) and left atrial volume (LAV), as well as a decrease in mitral E/A ratio, tricuspid regurgitation velocity (TRV) and pulmonary valve acceleration time (PVAT). Comparative analyses for patients treated with a continuous- vs pulsatile-type LVAD support showed a greater degree of unloading with the latter type, as shown by the effect on LVEDD (-13.7% vs -33.7%, p = 0.0.004), EDV (-23.5% vs -41.2%, p = 0.015), ESV (-25.6% vs -57.6%, p = 0.001) and LAV (-25.2% vs -40.4%, p = 0.071). The hemodynamic effects of continuous vs pulsatile LVAD support were similar, as shown by their effect on mitral E/A ratio (-23.9% vs -39.9%, p = NS), TRV (-26.4% vs -23.8%, p = NS) and PVAT (28.5% vs 38.5%, p = NS). Only pulsatile support demonstrated a statistically significant percent change in mass (-6.3% vs -20.6%, p = 0.038). Continuous and pulsatile forms of mechanical support demonstrated equivalent reductions in myocardial tumor necrosis factor-alpha (TNF-alpha), total collagen and mycocyte size. Our findings show that, although there are differences between these 2 devices in magnitude of unloading, both forms of support effectively normalize cellular markers of the failing phenotype.

1079-102 Correlation between norepinephrine and epinephrine myocardial spillover and tumor necrosis factor-alpha in conventional versus off-pump coronary artery bypass surgery

1079-102 Correlation between norepinephrine and epinephrine myocardial spillover and tumor necrosis factor-alpha in conventional versus off-pump coronary artery bypass surgery

Simvastatin decreases myocardial tumor necrosis factor-α content in heart transplant recipients

Background: Statins improve patient survival and decrease rejection episodes in heart transplant recipients. We studied the effects of simvastatin treatment on myocardial tumor necrosis factor alpha (TNF- α) expression, a potent pro-inflammatory cytokine associated with hypertrophy and fibrosis in heart transplant recipients.

Inhibition of p38 MAPK decreases myocardial TNF-alpha expression and improves myocardial function and survival in endotoxemia.

The role of p38 mitogen-activated protein kinase (MAPK) activation in lipopolysaccharide (LPS)-induced myocardial dysfunction has not been clearly defined. Our aim was to investigate the contribution of p38 MAPK in myocardial tumor necrosis factor-alpha (TNF-alpha) expression, cardiac function and survival during acute endotoxemia in mice. Acute endotoxemia was induced by LPS (10 mg/kg, i.p.) in mice. Two hours after LPS treatment, left ventricular (LV) function was assessed. Phosphorylation of p38 MAPK was measured by Western blotting. TNF-alpha mRNA and protein levels were determined by semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. LPS rapidly increased phosphorylation of p38 MAPK, followed by TNF-alpha mRNA expression and protein expression in the LV myocardium. Pre-treatment of the p38 MAPK inhibitor SB202190 (2 mg/kg, i.p.) decreased TNF-alpha mRNA and protein by 65 and 36%, respectively (P<0.05). Immunohistochemical staining confirmed that cardiomyocytes were the major source of TNF-alpha production in the myocardium and blocking p38 MAPK activation inhibited TNF-alpha expression in response to LPS. Pre-treatment of SB202190 or a TNF-alpha antagonist etanercept (2 mg/kg, i.p) significantly reversed LPS-induced LV depression (P<0.05). LPS (20 mg/kg, i.p.) induced 94% mortality in mice within 72 h and pre-treatment with SB202190 and etanercept decreased LPS-induced mortality to 65 and 40%, respectively (P<0.01). p38 MAPK activation represents an important mechanism leading to myocardial TNF-alpha production and cardiac dysfunction during acute endotoxemia in mice. Our data suggest that p38 MAPK is a potential therapeutic target of endotoxemia.

On-pump coronary artery bypass surgery activates human myocardial NF-κB and increases TNF-α in the heart 1,2

Purpose. Myocardial tumor necrosis factor alpha (TNF) production and nuclear factor kappa B (NF-κB) activation has been demonstrated in chronic heart failure and experimental models of acute ischemia-reperfusion injury. Further, a cause and effect relationship has been established between these events and cardiomyocyte apoptosis following such conditions. It remains unknown, however, whether the myocardial injury associated with coronary artery bypass surgery (CAB) results in myocardial NF-κB activation and TNF production. We hypothesized that CAB with cardiopulmonary bypass (“on-pump”) activates human myocardial NF-κB and increases TNF in the heart. Methods Patients, 18 to 65 years of age, scheduled for elective cardiac surgery but without other preexisting disease were considered eligible for the study. Biopsies of human myocardium were obtained before and after cardiopulmonary bypass and myocardial TNF levels were determined by ELISA and cytotoxicity assay, and NF-κB activation was determined by electrophoretic mobility shift assay ( n = 6 patients). NF-κB activation was quantitated with gel densitometry. Results. The clinical characteristics of the study patients were as follows (means ± SEM): mean age (y) 50.0 ± 5.7, male 6 (100%), cardiopulmonary bypass time (min) 107 ± 37.7, cross-clamp time (min) 68 ± 17.6, number of CAB 3.0 ± 1.1, and length of hospital stay (d) 4.8 ± 0.9. Before CAB, myocardial TNF-α levels were 251 ± 22 pg/g and 33 ± 9 U/g, as determined by ELISA and cytotoxicity assay, respectively. Following CAB, human myocardial TNF-α levels increased to 892 ± 71 pg/g ( P = 0.0008) and 141 ± 11 U/g ( P = 0.0042), as determined by ELISA and cytotoxicity assay, respectively. Before CAB, the ratio of bound to unbound NF-κB DNA was 0.009 ± 0.0007 and after CAB the ratio was 0.24 ± 0.01 ( P < 0.0001). Conclusion. This study represents the initial demonstration that coronary artery bypass grafting results in an activation of NF-κB and an increase of TNF in the heart.

What is the Source of Increased Myocardial Tumor Necrosis Factor-alpha in Heart Failure?

What is the Source of Increased Myocardial Tumor Necrosis Factor-alpha in Heart Failure?

What is the source of increased myocardial tumor necrosis factor-alpha in heart failure?

What is the source of increased myocardial tumor necrosis factor-alpha in heart failure?

Anti–Tumor Necrosis Factor-Alpha Improves Myocardial Recovery After Ischemia and Reperfusion

Objectives. This study sought to assess the importance of locally released or paracrine myocardial tumor necrosis factor-alpha (TNF-alpha) in the evolution of postischemic myocardial dysfunction and to use immunohistochemical studies to localize TNF-alpha within the myocardium.Background. TNF-alpha is implicated as a systemic mediator in the development of myocardial ischemia–reperfusion injury by promoting leukocyte myocardial infiltration, and it has been shown to originate from noncardiac peripheral mononuclear cells. We have recently documented in a blood-free environment the release of TNF-alpha from the ischemic-reperfused myocardium.Methods. Isolated rat hearts undergoing 1 h of global cardioplegia-induced ischemia and 30 min of reperfusion were investigated with use of the modified Langendorff model. Hearts were randomly divided into three subgroups: group A, control group; and groups B and C, isolated hearts receiving cardioplegic solution containing monoclonal hamster antimurine TNF-alpha antibodies (group B) or hamster IgG (group C).Results. Significant amounts of TNF-alpha were detected in group A and group C effluent on 1 min of reperfusion (752 ± 212 and 958 ± 409 pmol/ml, respectively). However, in group B, TNF-alpha was below detectable levels. In this group, postischemic left ventricular peak systolic pressures, first derivative of the rise in left ventricular pressure (dP/dtmax), pressure-time integral, coronary flow and O2consumption improved (analysis of variance [ANOVA] p < 0.0001 for all variables) compared with values in groups A and C; creatine kinase levels decreased (p < 0.005); and myocardial structure was preserved. Immunohistochemical staining localized TNF-alpha to cardiac myocytes and to endothelial cells.Conclusions. Anti–TNF-alpha neutralizes local TNF-alpha release from cardiac myocytes after ischemia and improves myocardial recovery during reperfusion, indicating that postischemic paracrine TNF-alpha release plays an active role in myocardial dysfunction.