Tumor necrosis factor in congestive heart failure: A mechanism of disease for the new millennium?

doi:10.1016/S0033-0620(98)80028-5

Progress in Cardiovascular Diseases

Volume 41, Issue 1, Supplement 1, July–August 1998, Pages 25-30

https://doi.org/10.1016/S0033-0620(98)80028-5 Get rights and content

Tumor necrosis factor alpha (TNF-α), a protein belonging to the family of cytokines, is one of the leading mediators of the immune response to inflammation. Its widespread biological effects are modulated by two circulating binding proteins corresponding to the extracellular domain of the membrane receptors, namely soluble TNF receptors. TNF-α was first supposed to be linked with congestive heart failure (CHF) on a cachexia-inducing basis. In patients with advanced CHF, elevated levels of circulating TNF-α and soluble TNF receptors have been found. The pathophysiological implications of activation of the TNF system in CHF seem to rely mainly on its effects on the heart and the endothelium. TNF-α exerts a negative inotropic effect both directly and indirectly, this latter being mediated by enhancement of nitric oxide production. Moreover, TNF-α has been suggested to trigger the apoptotic process in cardiac myocytes. There is consensus on the detrimental role played by TNF-α in CHF further supported by the evidence of a temporal association between TNF activation and transition from asymptomatic to symptomatic CHF.

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Citation Excerpt :
The expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α is markedly and consistently increased in experimental models of myocardial infarction and in patients with heart failure (Herskowitz et al., 1995; Zhao and Zeng, 1997). A large number of reports have established the essential role of inflammatory cytokines in the progression of heart failure contributing to the processes of cardiac hypertrophy, fibrosis, and apoptosis (Yokoyama et al., 1993; Ceconi et al., 1998; Novoyatleva et al., 2014). B1 receptor deletion attenuates cardiac inflammation and fibrosis during experimental diabetic cardiomyopathy (Westermann et al., 2009).
The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats.
Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, and improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls.
The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor.
A nucleus-targeted alternately spliced Nix/Bnip3L protein isoform modifies nuclear factor κB (NFκB)-mediated cardiac transcription
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Citation Excerpt :
TNFα and NFκB both induce complex gene programs that can alter the homeostatic balance in favor of cell survival or cell death, depending upon pathophysiological context (25–27). Here, TNFα and NFκB induce gene expression favoring cell death pathways in cardiomyocytes, consistent with their proposed role in cardiomyocyte apoptosis and heart failure (30, 31). The net effect of sNix on NFκB p65/RelA-mediated gene expression is to reorient TNFα-induced NFκB signaling in favor of cytoprotection.
Several Bcl2 family proteins are expressed both as mitochondrial-targeted full-length and as cytosolic truncated alternately spliced isoforms. Recombinantly expressed shorter Bcl2 family isoforms can heterotypically bind to and prevent mitochondrial localization of their full-length analogs, thus suppressing their activity by sequestration. This “sponge” role requires 1:1 expression stoichiometry; absent this an alternate role is suggested. Here, RNA sequencing revealed coordinate regulation of BH3-only protein Nix/Bnip3L (Nix) and its alternately spliced soluble form (sNix) in hearts, but relative sNix/Nix expression of ∼1:10. Accordingly, we examined other putative functions of sNix. Although Nix expressed in H9c2 rat myoblasts localized to mitochondria, sNix showed variable cytoplasmic and nuclear distribution. Tumor necrosis factor α (TNFα) induced rapid and complete sNix nucleoplasmic translocation concomitant with nuclear translocation of the p65/RelA subunit of NFκB. sNix co-localized and co-precipitated with p65/RelA after TNFα stimulation; TNFα-induced sNix nuclear translocation did not occur in p65/RelA null murine embryonic fibroblasts. ChIP sequencing of TNFα-stimulated H9c2 cells revealed sNix suppression of p65/RelA binding to a subset of weaker DNA binding sites, accounting for its ability to alter gene expression in cultured cells and in vivo mouse hearts. These findings reveal TNFα-stimulated cytoplasmic-nuclear shuttling of the alternately spliced non-mitochondrial Nix isoform and uncover a role for sNix as a modulator of TNFα/NFκB-stimulated cardiac gene expression. Transcriptional co-regulation of sNix and Nix, combined with sNix posttranslational regulation by TNFα, comprises a previously unknown mechanism for molecular cross-talk between extrinsic death receptor and intrinsic mitochondrial apoptosis pathways.
Background: Functions of short, cytosolic splice Bcl2 protein isoforms are unknown.
Results: TNFα provokes complexing of the splice isoform of Nix (sNix) to NFκB p65/RelA, their nuclear translocation, gene promoter binding, and suppressed expression.
Conclusion: sNix is a modifier of TNFα-mediated cardiomyocyte gene transcription.
Significance: sNix-TNFα interactions comprise a previously undescribed mechanism for cross-talk between extrinsic and intrinsic apoptosis pathways.
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TNFα is crucially involved in the pathogenesis and progression of atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFα and its downstream signal transduction cascade following activation of its two receptor subtypes is characterized, with special emphasis on the cardiovascular system.
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In the myocardium, TNFα contributes to reversible and irreversible ischemia/reperfusion injury, post-myocardial infarction remodeling and heart failure development. Simultaneously, TNFα also contributes to cardioprotection by ischemic conditioning. Emphasis is placed on such ambivalent (detrimental vs. beneficial) role of TNFα, which appears to be dose- and time-dependent and in part related to the activation of the specific receptor subtype. Given the ambivalent role of TNFα and its receptors, it is not surprising that clinical trials using compounds that antagonize TNFα revealed ambiguous and largely disappointing results in cardiovascular disease, notably in heart failure.
Future perspectives to antagonize and/or potentially recruit TNFα in the cardiovascular system are critically discussed.
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Currently, there are 5 million individuals with chronic heart failure (CHF) in the United States who have poor clinical outcomes, including high death rates. Observational studies have indicated a reverse epidemiology of traditional cardiovascular risk factors in CHF; in contrast to trends seen in the general population, obesity and hypercholesterolemia are associated with improved survival. The temporal discordance between the overnutrition (long-term killer) and undernutrition (short-term killer) not only can explain some of the observed paradoxes but also may indicate that malnutrition, inflammation, and oxidative stress may play a role that results in protein-energy wasting contributing to poor survival in CHF. Diminished appetite or anorexia and nutritional deficiencies may be both a cause and a consequence of this so-called malnutrition-inflammation-cachexia (MIC) or wasting syndrome in CHF. Neurohumoral activation, insulin resistance, cytokine activation, and survival selection–resultant genetic polymorphisms also may contribute to the prominent inflammatory and oxidative characteristics of this population. In patients with CHF and wasting, nutritional strategies including amino acid supplementation may represent a promising therapeutic approach, especially if the provision of additional amino acids, protein, and energy includes nutrients with anti-inflammatory and antioxidant properties. Regardless of the etiology of anorexia, appetite-stimulating agents, especially those with anti-inflammatory properties such as megesterol acetate or pentoxyphylline, may be appropriate adjuncts to dietary supplementation. Understanding the factors that modulate MIC and body wasting and their associations with clinical outcomes in CHF may lead to the development of nutritional strategies that alter the pathophysiology of CHF and improve outcomes.
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There are a number of factors related to heart failure pathophysiology and treatment that influence nutrient requirements for patients. These include catabolism, inflammation, oxidative stress, diuretic use, and presence of comorbidities. On the other hand, there is evidence that specific nutrients can alter heart failure pathophysiology. This article reviews the current evidence for nutritional recommendations regarding sodium and fluid restriction, macro- and micronutrient intake, and dietary changes required by the presence of common comorbidities.
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2007, American Journal of the Medical Sciences
Citation Excerpt :
In rodent models of MI, TNF-α expression is significantly upregulated in the infarcted myocardium as well as in the noninfarcted myocardium.69 TNF-α can stimulate inflammatory protein synthesis, macrophage phagocytosis and cell growth, differentiation, and apoptosis.70 In the infarcted myocardium, elevated NADPH oxidase is spatially coincident with activated NF-κB and enhanced TNF-α expression in the inflammatory cells.66
Extensive cardiac remodeling after myocardial infarction (MI) contributes significantly to ventricular dysfunction. Factors regulating left ventricular remodeling at different stages after MI are under investigation. There is growing recognition and experimental evidence that oxidative stress mediated by reactive oxygen species plays a role in the pathogeneses of myocardial repair/remodeling in various cardiac diseases. After acute MI, oxidative stress is developed in both infarcted and noninfarcted myocardium. Accumulating evidence has demonstrated that oxidative stress participates in several aspects of cardiac repair/remodeling after infarction that include cardiomyocyte apoptosis, inflammatory/fibrogenic responses, and hypertrophy. The exact pathways on reactive oxygen species–mediated myocardial remodeling are under investigation. The therapeutic potential of oxidative stress-directed drugs in myocardial remodeling after infarction has not been fully realized.

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^*: Supported in part by the European Commission Biomed-2 Concerted Action, grant no. 95-0838, The New Ischemic Syndromes.

View full text

Tumor necrosis factor in congestive heart failure: A mechanism of disease for the new millennium?*

J Biol Chem

Biochem Biophys Res Commun

Cell

Cell

Cell

J Biol Chem

Am J Cardiol

Res Immunol

An endotoxin-induced serum factor that causes necrosis of tumors

Oligomeric tumor necrosis factor alpha slowly converts into inactive forms at bioactive levels

Biochem J

The acute and chronic pathophysiological effects of TNF: Mediation of septic shock and wasting

Cytokines and the response to infection

J Pathol

Induction of a macrophage-like nitric oxide synthase in cultured rat aortic endothelial cells. IL-1β-mediated induction regulated by tumor necrosisfactor-α and IFN-γ

J Immunol

Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium

Br J Pharmacol

Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p60) and its soluble derivative, tumor necrosis factor-binding protein

DNA Cell Biol

A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins

Science

Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

J Exp Med

Shedding of tumor necrosis factor receptors by activated human neutrophils

J Exp Med

Complementary DNA cloning of a receptor for tumor necrosis factor and demonstration of a shed of the receptor

Diseases of the Heart

Induction and potential biological relevance of a Ca²⁺-independent nitric oxide synthase in the myocardium