Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heart failure is a common problem associated with considerable mortality and morbidity. The mechanisms underlying the heart failure syndrome, which remain poorly understood, may involve an inflammatory process. Nitric oxide (NO) and various cytokines could play an important role in this inflammatory process. Recent evidence has emerged in both animal models and humans suggesting that both of these mediators may play an important role in heart failure. NO is synthesized by the NO synthase family of enzymes. Two of these enzymes are constitutive, endothelial NO synthase and neuronal NO synthase. The third enzyme, inducible NO synthase, is capable of producing large amounts of NO once induced by mediators such as interleukin (IL)-1, IL-2, IL-6, tumour necrosis factor (TNF)-alpha, and interferon-gamma. Endothelial NO synthase is present in the heart in the endocardium, cardiac myocytes, and cardiac conduction tissue. Inducible NO synthase is present in cardiac myocytes, endocardium, vascular smooth muscle cells, and infiltrating inflammatory cells. Evidence from both animal models and patients suggests that NO exerts a negative inotropic effect. Increased inducible NO synthase, TNF-alpha, and IL-6 have been found in patients with heart failure in several studies. In other studies, decreased endothelial NO synthase was found in patients with heart failure. TNF-alpha and IL-6 may be produced in heart failure and may induce inducible NO synthase, resulting in NO production, which acts as a negative inotrope. Endothelial NO synthase may be decreased as a result of downregulation by TNF-alpha or inducible NO synthase. The possible role of these mediators in heart failure needs further evaluation because these findings could have novel therapeutic implications.
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PMID:The role of nitric oxide and cytokines in heart failure. 934 18

Cytokines have been associated with the pathogenesis of acute coronary syndromes and chronic heart failure (CHF), which are both associated with cardiomyocyte loss. In CHF, increased serum concentrations of proinflammatory cytokines, including tumour necrosis factor alpha (TNF-alpha) and also soluble TNF receptor have been found. Both TNF and Fas-ligand have been able to induce programmed cell death (apoptosis) of cardiomyocytes in various experimental studies. In ischaemic conditions of the heart, increased serum levels of soluble Fas receptor have been found. The proinflammatory cytokines interleukin 1 (IL-1), IL-2 and interferon-gamma can induce TNF production from target cells, including myocytes. TNF and some other cytokines are able to induce nitric oxide production, which depresses cardiac function and can induce apoptosis. However, anti-inflammatory cytokines such as IL-10, IL-4 and IL-13, secreted by T-helper type 2 lymphocytes and other cells, inhibit the production of proinflammatory cytokines. Preliminary studies suggest that cardiotrophin-1, produced by cardiomyocytes, is able to inhibit cytokine-induced cardiomyocyte apoptosis in vitro. As growth hormone is able to inhibit the production of proinflammatory cytokines in many cell types, it may also play an important role in the regulation of apoptosis induced by these cytokines. When the cytokine-induced pathways leading to altered gene expression of cardiomyocytes are understood, this knowledge may aid in the development of drugs that prevent progressive cardiomyocyte loss, in particular by inhibiting cytokine-induced apoptosis.
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PMID:Cytokines and cardiomyocyte death. 937 93

Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
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PMID:Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. 944 16

Endogenous nitric oxide (NO) signalling pathways within the myocardium depress myocardial contractile function in septic shock and some cardiomyopathies. We have explored the role of NO synthases (NOSs) in mediating the cardiodepressant actions of interferon-gamma (IFN-gamma) and lipopolysaccaride (LPS) in rat papillary muscle. Muscles from the right ventricle were electrically stimulated (0.2 Hz) at 30 degrees C and isometric contraction monitored. Exposure to IFN-gamma and LPS for 15 h in vitro significantly decreased the peak tension (PT for IFN-gamma + LPS, from 0.13 +/- 0.03 to 0.07 +/- 0.02 g) and rate of tension development (dT/dt for IFN-gamma + LPS, from 1.78 +/- 0.36 to 1.17 +/- 0.28 g/s) compared to untreated controls, and this was prevented by dexamethasone (1 microM) and partly reversed by a non-specific NOS inhibitor, NG-nitro-L-arginine (NOLA, 30 microM). Likewise, the maximum inotropic response of the papillary muscles to isoprenaline (0.001-10 microM) decreased significantly after 15 h treatment with IFN-gamma and LPS (PT from 83 +/- 18 to 28 +/- 6%; +dT/dt from 83 +/- 12 to 31 +/- 7%; -dT/dt from 83 +/- 12 to 38 +/- 6%). Again, the depressant effects of IFN-gamma and LPS on inotropic responsiveness to isoprenaline were completely prevented by pretreatment with dexamethasone (1 microM), by a specific inhibitor of NOS2, mercaptoethylguanidine (MEG, 30 microM) and by NOLA. Whereas dexamethasone and NOLA protected against the attenuation of baseline contractions induced by LPS and IFN-gamma, MEG did not. Western blot analysis of cardiac myocytes showed that there was no constitutive expression of NOS2, but IFN-gamma and LPS induced expression of NOS2, and this was prevented by dexamethasone. Thus IFN-gamma, in the presence of LPS, reduced papillary muscle contraction and decreased responsiveness to beta-adrenoceptor stimulation through induction of NOS2 in the muscle. Increased NO production may contribute to the cardiac depression during septic shock and anti-cancer therapy with cytokines, and perhaps in heart failure.
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PMID:Cardiodepressant effects of interferon-gamma and endotoxin reversed by inhibition of NO synthase 2 in rat myocardium. 961 39

Viral myocarditis is an important cause of heart failure and dilated cardiomyopathy. T lymphocytes are implicated in myocardial damage in murine models of coxsackievirus B3 (CVB3) myocarditis. We used knockout mice lacking CD4 (CD4(-/-)), CD8 (CD8(-/-)), both coreceptors (CD4(-/-)CD8(-/-)), or the T-cell receptor beta chain (TCRbeta(-/-)) to address the contribution of T-cell subpopulations to host susceptibility to CVB3 myocarditis. Severity of disease was magnified in CD8(-/-) mice but attenuated in CD4(-/-) mice, consistent with a pathogenic role for CD4(+) lymphocytes. Elimination of both CD4 and CD8 molecules from T lymphocytes by genetic knockout better protected mice from myocarditis, demonstrating that both CD4(+) and CD8(+) T cells contribute to host susceptibility. The same benefit occurred in TCRbeta(-/-) mice, with prolonged survival and minimal myocardial disease observed after CVB3 infection. Elevated interferon-gamma and decreased tumor necrosis factor-alpha expression are associated with attenuated myocardial damage in CD4(-/-)CD8(-/-) mice. These results show that the presence of TCRalphabeta(+) T cells enhances host susceptibility to myocarditis. The severity of myocardial damage and associated mortality are dependent on the predominant T-cell type available to respond to CVB3 infection. One mechanism by which CD4(+) and CD8(+) T-cell subsets influence the pathogenesis of myocarditis may involve specific cytokine expression patterns.
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PMID:Susceptibility to myocarditis is dependent on the response of alphabeta T lymphocytes to coxsackieviral infection. 1048 59

We tested the hypothesis that the inflammatory cytokines can regulate fibroblast extracellular matrix metabolism. Neonatal and adult rat cardiac fibroblasts cultures in vitro were exposed to interleukin (IL)-1beta (4 ng/mL), tumor necrosis factor-alpha (TNF-alpha; 100 ng/mL), IL-6 (10 ng/mL), or interferon-gamma (IFN-gamma; 500 U/mL) for 24 hours. IL-1beta, and to a lesser extent TNF-alpha, decreased collagen synthesis, which was measured as collagenase-sensitive [(3)H]proline incorporation, but had no effect on cell number or total protein synthesis. IL-1beta decreased the expression of procollagen alpha(1)(I), alpha(2)(I), and alpha1(III) mRNA, but increased the expression of procollagen alpha(1)(IV), alpha(2)(IV), and fibronectin mRNA, indicating a selective transcriptional downregulation of fibrillar collagen synthesis. IL-1beta and TNF-alpha each increased total matrix metalloproteinase (MMP) activity as measured by in-gel zymography, causing specific increases in the bands corresponding to MMP-13, MMP-2, and MMP-9. IL-1beta increased the expression of proMMP-2 and proMMP-3 mRNA, suggesting that increased metalloproteinase activity is due, at least in part, to increased transcription. The effects of IL-1beta were not dependent on NO production. Thus, IL-1beta and TNF-alpha decrease collagen synthesis and activate MMPs that degrade collagen. These observations suggest that IL-1beta and TNF-alpha may contribute to ventricular dilation and myocardial failure by promoting the remodeling of interstitial collagen.
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PMID:Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. 1086 17

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.
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PMID:Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation. 1089 97

Proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), are elevated during cardiopulmonary bypass (CPB), heart failure, and inflammatory cardiac and systemic diseases. Elevated TNF-alpha has been linked to diminished cardiac function, decreased systemic vascular resistance, as well as renal and pulmonary dysfunction. It is understood that myocardial tissues can express TNF-alpha, which results in the induction of inducible nitric oxide synthase (iNOS) leading to a significant decline in cardiac function and other direct effects. The hypothesis of this study was to determine if TNF-alpha would stimulate iNOS and its product nitric oxide (NO) similarly in immortalized macrophage and cardiac myocytes. Cultured macrophages (RAW 264.7) and cardiac myocytes (HL-1) were placed into two treatment groups and a control. The treatments included: (1) TNF-alpha and lipopolysaccharide (LPS); and (2) LPS, TNF-alpha, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) incubated for 8 h. The macrophage expression of iNOS increased by 365% (p < 0.01) and its product, NO, increased proportionally. The expression of iNOS in the cardiac myocyte did not increase with TNF-alpha and LPS. However, with the addition of IFN-alpha and IL-1beta iNOS increased to 140% of control (p < 0.05). Myocyte cGMP and NO did not increase significantly with TNF-alpha treatment. This study suggests that HL-1 myocyte iNOS cannot be induced by TNF-alpha, unlike macrophage iNOS. Furthermore, the resultant cardiac dysfunction, secondary to proinflammatory cytokines effects, is regulated via diverse pathways.
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PMID:Comparison of tumor necrosis factor-alpha effect on the expression of iNOS in macrophage and cardiac myocytes. 1119 10

Release of bacterial endotoxin and cytokines induce cardiac failure during sepsis. We investigated the direct effects of E. coli endotoxin (lipopolysaccharide, LPS) and cytokines induced by LPS on the cardiac myocyte gene program. For in vivo-experiments adult Wistar rats were given 600 microg/day LPS i.v. for 24 h or 7 days. In addition, cultured adult rat cardiac myocytes were treated with LPS, interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNFalpha), interferon-gamma (IFNgamma) or IL-6 for 24 h. mRNA expression was evaluated for cardiac-alpha-actin (cAct), skeletal-alpha-actin (skAct), beta- and alpha-myosin heavy chain (MHC). LPS induced betaMHC-mRNA 3.6-fold and repressed alphaMHC 2.7-fold and cAct 2.5-fold after 24 h in vivo. Up-regulation of betaMHC (3-fold) and repression of cAct (2.5-fold) were still observed after 7 days LPS infusion, whereas alphaMHC-mRNA levels had returned to normal. At the protein level, increased expression of betaMHC by LPS treatment occurred already after 24 h and was maintained thereafter. LPS had no influence on skAct-mRNA. Similar changes in contractile protein mRNA expression were observed in LPS-treated cardiomyocytes in culture, whereas the tested cytokines either activated (IL-1beta, IFNgamma) or repressed (TNFalpha, IL-6) both MHC-isoforms and cAct. In conclusion, LPS and proinflammatory cytokines induce changes in contractile protein expression that may contribute to the acute heart failure observed during endotoxaemia.
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PMID:Endotoxin and cytokines alter contractile protein expression in cardiac myocytes in vivo. 1168 Jun 26

Osteopontin (OPN), also called cytokine Eta-1, expressed in the myocardium co-incident with heart failure plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Angiotensin II (Ang II) and inflammatory cytokines are increased in the heart following MI. We studied the involvement of mitogen-activated protein kinases (ERK1/2, JNKs, p38 kinase) and reactive oxygen species (ROS) in Ang II- and cytokine-induced OPN gene expression in adult rat cardiac fibroblasts. Ang II alone increased OPN mRNA (3.3 +/- 0.3-folds; P < 0.05; n = 7), while interleukin-1beta (IL-1beta), tumor necrosis factor (TNF-alpha), and interferon-gamma (IFN-gamma) had no effect. A combination of Ang II with IL-1beta or TNF-alpha, not IFN-gamma, increased OPN mRNA more than Ang II alone. Nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), alone or in combination with Ang II had no effect. Diphenylene iodonium (DPI), inhibitor of NAD(P)H oxidase, and tiron, superoxide scavenger, inhibited Ang II- and Ang II+ IL-1beta-stimulated increases in OPN mRNA. Ang II activated ERK1/2 within 5 min of treatment, not JNKs. IL-1beta activated ERK1/2 and JNKs within 15 min of treatment. A combination of Ang II and IL-1beta activated ERK1/2 within 5 min of treatment. None of these stimuli activated p38 kinase. DPI almost completely inhibited Ang II + IL-1beta-stimulated activation of ERK1/2, while partially inhibiting JNKs. PD98059, ERK1/2 pathway inhibitor, and SP600125, JNKs inhibitor, partially inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. A combination of PD98059 and SP600125 almost completely inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. Thus, Ang II alone increases OPN expression, while IL-1beta and TNF-alpha act synergistically with Ang II to increase OPN mRNA possibly via NO independent mechanisms. The synergistic increase in OPN mRNA involves ROS-mediated activation of ERK1/2 and JNKs, not P38 kinase, pathways in cardiac fibroblasts.
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PMID:ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. 1475 45


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