Tumor Necrosis Factor-α–Converting Enzyme and Tumor Necrosis Factor-α in Human Dilated Cardiomyopathy

Satoh, Mamoru; Nakamura, Motoyuki; Saitoh, Hideo; Satoh, Hidetoshi; Maesawa, Chihaya; Segawa, Ikuo; Tashiro, Atsushi; Hiramori, Katsuhiko

doi:10.1161/01.cir.99.25.3260

Cited by 114 publications

(72 citation statements)

References 24 publications

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“…8,27,28 Our previous studies have demonstrated that TNF-a cascade is activated in human DCM via expression of its converting enzyme and iNOS and that this activation may be related to the clinical severity of DCM. 5,6,29 Although this study could not confirm a direct causal relationship between activation of the TLR4-signaling pathway and LV dysfunction induced by inflammatory mediators, the LPS-challenged mouse model has demonstrated that TLR4 is tightly linked with NF-kB activation and expression of proinflammatory cytokines such as interleukin 1 and TNF-a in the heart. 30 These inflammatory mediators have been shown in various reports to produce LV dysfunction.…”

Section: Discussioncontrasting

confidence: 60%

“…30 These inflammatory mediators have been shown in various reports to produce LV dysfunction. 5,6,29,31,32 Nemoto et al 33 have recently reported that LPS challenge resulted in depression of LV systolic function in wild-type mice, whereas no significant changes in LV systolic function were noted in TLR4-deficient mice. The activated TLR4-signaling pathway in the heart may therefore be linked to inflammatory mediators (eg proinflammatory cytokines and iNOS) and to cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…4 Our previous study has reported that myocardial expression levels of tumor necrosis factor-a (TNF-a) and EV RNA were increased in patients with DCM regardless of etiology of left ventricular (LV) dysfunction. 5,6 It is likely that an immune response against viral pathogens is important in the pathogenesis of DCM. However, the precise mechanism underlying tissue injury in virus-mediated cardiomyopathy is not clear.…”

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confidence: 99%

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Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Satoh

Nakamura

Akatsu

et al. 2004

Laboratory Investigation

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Expressions of innate immune response proteins, most notably proinflammatory cytokines, against enteroviral (EV) infection have been documented in the heart of human dilated cardiomyopathy (DCM). Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of proinflammatory cytokines implicated the etiology of DCM. We sought to determine whether EV replication activates TLR4-dependent immune response in myocardium obtained from patients with DCM. Endomyocardial biopsy tissues were obtained from 56 patients with DCM and 10 controls. Levels of plus-and minus-strand EV RNA and TLR4 mRNA were measured by real-time RT-PCR. Immunohistochemical analysis was performed to identify the cellular source of EV capsid protein VP1 and TLR4. Both plus-and minus-strand EV RNA were detected in 19 DCM patients (34%). Neither strand of EV RNA was detected in controls. TLR4 mRNA levels were higher in DCM patients than in controls (Po0.001). A positive correlation was found between TLR4 levels and each strand type of EV RNA in EV RNApositive patients (plus-strand vs TLR4: r ¼ 0.69, Po0.001; minus-strand vs TLR4: r ¼ 0.65, P ¼ 0.002). VP1/TLR4 double staining showed extensive colocalization of VP1 and TLR4 proteins in cytoplasm of cardiac myocytes in myocardium obtained from DCM patients. EV RNA-positive patients showed lower systolic function and larger ventricular volume compared with EV RNA-negative patients left ventricular ejection fraction (LVEF): P ¼ 0.002; left ventricular end-systolic diameter (LVESD): P ¼ 0.004). The DCM subgroup with high TLR4 levels showed lower LVEF and larger LVESD than the subgroup with TLR4 levels (both Po0.001). This study suggests that myocardial expression of TLR4 associates with EV replication in human DCM. EV RNA and TLR4 mRNA levels may correlate with LV dysfunction in DCM. The expression of TLR4 against EV replication may be involved in the pathogenesis of DCM.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Satoh

Nakamura

Akatsu

et al. 2004

Laboratory Investigation

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“…Expression of TNF␣-converting enzyme (TACE), which cleaves TNF and its receptors from the cell surface, has been demonstrated in human atherosclerotic plaques (44). TACE levels have also been shown to correlate with the degree of left ventricular systolic dysfunction in patients with dilated cardiomyopathy (45), and it has been suggested that circulating levels of sTNFRII may be a surrogate marker for worsening left ventricular function and/or remodeling (18).…”

Section: Mattey Et Almentioning

confidence: 99%

Circulating levels of tumor necrosis factor receptors are highly predictive of mortality in patients with rheumatoid arthritis

Mattey

Glossop

Nixon

et al. 2007

Arthritis & Rheumatism

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Objective. To investigate whether circulating levels of soluble tumor necrosis factor receptors (sTNFR) are predictive of mortality in rheumatoid arthritis (RA).Methods. Levels of sTNFRI and sTNFRII at study entry were quantified using enzyme-linked immunosorbent assays in sera from 401 white patients with RA followed up for 13 years. Patients were tracked via the National Health Service Central Register, and the relationship between sTNFR levels and mortality was analyzed using a Cox proportional hazards regression model. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.Results. At the end of the followup period, 132 (32.9%) of 401 patients had died. Of these, 64 (48.5%) died of cardiovascular disease (CVD). Significant associations between all-cause mortality and baseline levels of sTNFRI and sTNFRII were identified in men (HR 1.7 [95% CI 1.2-2.4] and HR 1.18 [95% CI 1.05-1.32], respectively) and women (HR 1.33 [95% CI 0.99-1.8] and HR 1.14 [95% CI 1.02-1.28], respectively). Analysis including levels of both sTNFRI and sTNFRII indicated that the sTNFRII level was the best overall predictor of mortality. Multivariate analysis also revealed that the sTNFRII level was a predictor of all-cause and CVD mortality independently of age, sex, disease duration, C-reactive protein level, erythrocyte sedimentation rate, rheumatoid factor, nodular disease, modified Health Assessment Questionnaire score, taking CVD drugs, and smoking.Conclusion. Our data indicate that serum levels of sTNFR are powerful predictors of mortality in RA. Elevated levels are particularly associated with mortality due to CVD and may be useful for identifying patients at increased risk of premature death.

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“…Shedding of TNF-␣ is mediated predominantly by TACE (ADAM17), 24 and TACE activity is strongly associated with ventricular dilatation and cardiac dysfunction in human heart failure. 11 TNF-␣ receptor II, p75, can be released in soluble form by TACE or on binding to TNF-␣. 25 Compared with TNF-␣, soluble p75 level has a longer half-life and is easily detectable and thus a preferred measure of overall TACE bioactivity.…”

Section: Fedak Et Al Timp-3 Deficiency and Cardiomyopathy 2405mentioning

confidence: 99%

TIMP-3 Deficiency Leads to Dilated Cardiomyopathy

et al. 2004

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Background-Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. Methods and Results-Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-␣ cytokine system, molecular hallmarks of human myocardial remodeling. Conclusions-TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.

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Tumor Necrosis Factor-α–Converting Enzyme and Tumor Necrosis Factor-α in Human Dilated Cardiomyopathy

Abstract: This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-alpha expression in both mRNA and protein levels in clinically advanced DCM.

Cited by 114 publications

References 24 publications

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Circulating levels of tumor necrosis factor receptors are highly predictive of mortality in patients with rheumatoid arthritis

TIMP-3 Deficiency Leads to Dilated Cardiomyopathy

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