scholarly journals Inhibition of Tumor Necrosis Factor-α Improves Postischemic Recovery of Hypertrophied Hearts

Circulation ◽  
2001 ◽  
Vol 104 (suppl_1) ◽  
Author(s):  
Christof Stamm ◽  
Ingeborg Friehs ◽  
Douglas B. Cowan ◽  
Adrian M. Moran ◽  
Hung Cao-Danh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Intracellular Calcium ◽  
Tumor Necrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Calcium Handling ◽  
Tnf Α ◽  
Postischemic Recovery ◽  
Necrosis Factor

Background Tumor necrosis factor (TNF)-α has been implicated in the pathogenesis of heart failure and ischemia-reperfusion injury. Effects of TNF-α are initiated by membrane receptors coupled to sphingomyelinase signaling and include altered metabolism and calcium cycling, contractile dysfunction, and cell death. We postulate that pressure-overload hypertrophy results in increased myocardial TNF-α expression and that it contributes to decreased contractility in hypertrophied infant hearts subjected to ischemia-reperfusion. Methods and Results Neonatal rabbits underwent aortic banding to induce LV hypertrophy. Myocardial TNF-α protein expression increased progressively with LV hypertrophy. Serum TNF-α was detected only after the onset of heart failure. Before onset of ventricular dilatation and heart failure (determined by serial echocardiograms), hearts from aortic banded and age-matched control rabbits were perfused in the Langendorff mode and subjected to 45 minutes of ischemia and 30 minutes of reperfusion. Postischemic recovery was impaired in hypertrophied hearts, but addition of neutralizing anti-rabbit TNF-α antibody to cardioplegia and perfusate solutions restored postischemic function. This effect was mimicked by treatment with the ceramidase inhibitor N -oleoyl ethanolamine. TNF-α inhibition also was associated with faster postischemic recovery of phosphocreatine, ATP, and pH as assessed by 31 P nuclear magnetic resonance spectroscopy. Intracellular calcium handling, measured by Rhod 2 spectrofluorometry, demonstrated lower diastolic calcium levels and higher systolic calcium transients in anti-TNF-α treated hearts. Conclusions TNF-α is expressed in myocardium during compensated pressure-overload hypertrophy and contributes to postischemic myocardial dysfunction. Inhibition of TNF-α signaling significantly improves postischemic contractile function, myocardial energetics, and intracellular calcium handling.

Abstract P210: Central Blockade Of Tumor Necrosis Factor-Á-Converting Enzyme (tace) Ameliorates Neuroinflammation, Sympathetic Excitation And Cardiac Dysfunction In Heart Failure Rat

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yang Yu ◽  
Baojian Xue ◽  
Hanzeng Li ◽  
Qing Chen ◽  
Mingxuan Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Cardiac Dysfunction ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Male Rats ◽  
Tnf Α ◽  
Necrosis Factor

TACE is a key metalloprotease involved in ectodomain shedding of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-α. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to the sympathetic excitation in heart failure (HF). Additionally, the upregulated TGF-α in the PVN transactivates the epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK) 1/2 in HF. Here we sought to determine whether central inhibition of TACE attenuates neuroinflammation and prevents the progress of HF. Male rats underwent coronary artery ligation to induce HF or sham surgery (Sham). These rats were treated with bilateral PVN microinjection of a TACE siRNA or control siRNA while some rats received a 4-week intracerebroventricular (ICV) infusion of TACE inhibitor TAPI-0 or vehicle. Compared with Sham rats, HF rats treated with control siRNA, had higher (*P<0.05) levels of TNF-α (7.88±1.32* vs 2.77±0.98 pg/mL) and TGF-α (28.27±2.76* vs 11.62±2.48 pg/mL) in cerebrospinal fluid, and increased mRNA expression of TACE (2.53±0.30* vs 1.04±0.12), TNF-α (3.43±0.55* vs 1.03±0.11), TNF-α receptor 1 (2.32±0.27* vs 1.07±0.19), cyclooxygenase-2 (2.96±0.31* vs 1.10±0.19) and TGF-α (2.68±0.41* vs 1.06±0.14) in the PVN, but these levels were markedly reduced (39-54%*) in TACE siRNA-treated HF rats. Compared with control HF rats, HF rats treated with TACE siRNA had reduced expression of phosphorylated (p-) NF-κB p65 (1.27±0.14 vs 0.84±0.07*), p-EGFR (0.52±0.05 vs 0.37±0.04*) and p-ERK1/2 (1.06±0.10 vs 0.62±0.09*) in the PVN. Moreover, the elevated plasma norepinephrine levels, lung/body weight, heart/body weight and left ventricular (LV) end-diastolic pressure along with decreased LV dP/dt max in HF rats-treated with control siRNA were significantly attenuated in HF rats treated with TACE siRNA. Treatments with TACE siRNA in the PVN also improved the indicators of cardiac hypertrophy and fibrosis of HF. ICV infusion of TAPI-0 had the similar effects with PVN TACE siRNA on these variables in HF. These data indicate that central interventions suppressing TACE activity ameliorate neuroinflammation, sympathetic activation and cardiac dysfunction in HF.

Abstract P136: Effects Of Sex Hormones On The Hemodynamic And Sympathetic Responses To Centrally Administered Tumor Necrosis Factor-α In Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Yiling Cao ◽  
Baojian Xue ◽  
Yang Yu ◽  
Alan K Johnson ◽  
Shun-Guang Wei
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Sex Hormones ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Female Rats ◽  
Tnf Α ◽  
Sympathetic Responses ◽  
Factor Α ◽  
Necrosis Factor

Inflammation plays an important role in the pathophysiology of cardiovascular dysfunction and neurohumoral excitation in heart failure and hypertension. Growing evidence has demonstrated significant sex differences in the inflammatory response and immune processes, with estrogen exerting an anti-inflammatory effects and testosterone potentially having pro-inflammatory influence. We previously reported that central administration of tumor necrosis factor-α (TNF-α) elicited different effects on blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in male and female rats. Whether the sex steroids estrogen and testosterone contribute to the observed differences in TNF-α-induced hemodynamic and sympathetic responses remains unknown. We hypothesized that estrogen protects against TNF-α-induced sympathetic excitation and pressor responses while testosterone enhances these excitatory outcomes in response to TNF-α. Female or male Sprague Dawley rats (10-12 weeks) anesthetized with ketamine plus xylazine underwent bilateral ovariectomy or castration, respectively, 2 weeks prior to study. Sham-operated (Sham) female or male animals served as controls. TNF-α (100 ng) was administered intracerebroventricularly (ICV). BP (mmHg), HR (bpm) and RSNA (% change) were recorded in urethane anesthetized rats. In ovariectomized female rats (n=6), ICV TNF-α induced significantly (*p<0.05 vs. Sham) larger increases in BP (19.3 ± 1.4* vs. 12.8 ± 1.2 ), HR (76.3 ± 4.8* vs. 51.5 ± 4.3) and RSNA (104.8 ± 6.9* vs. 72.4 ± 5.1), compared with Sham-female rats, that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In castrated male rats (n=6), ICV TNF-α-elicited significantly smaller increases in BP (15.2 ± 1.3* vs. 21.8 ± 1.6), HR (57.7 ± 4.2* vs. 82.6 ± 4.1) and RSNA (72.6 ± 4.3* vs. 110.3 ± 4.7), compared with Sham-male animals. These data indicate a distinct role of sex hormones estrogen and testosterone in central inflammation-driven cardiovascular and sympathetic activation and suggest a protective effect of estrogen and a harmful effect of testosterone in the development of hypertension and heart failure.

Tumor necrosis factor-α in ischemia and reperfusion injury in rat lungs

1998 ◽  
Vol 85 (6) ◽  
pp. 2005-2011 ◽  
Author(s):  
Pavel L. Khimenko ◽  
G. J. Bagby ◽  
J. Fuseler ◽  
Aubrey E. Taylor
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ischemia Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Microvascular Damage ◽  
Rat Lungs ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

The effects of both recombinant rat tumor necrosis factor-α (TNF-α) and an anti-TNF-α antibody were studied in isolated buffer-perfused rat lungs subjected to either 45 min of nonventilated [ischemia-reperfusion (I/R)] or air-ventilated (V˙/R) ischemia followed by 90 min of reperfusion and ventilation. In the I/R group, the vascular permeability, as measured by the filtration coefficient ( K fc), increased three- and fivefold above baseline after 30 and 90 min of reperfusion, respectively ( P < 0.001). Over the same time intervals, the K fc for theV˙/R group increased five- and tenfold above baseline values, respectively ( P < 0.001). TNF-α measured in the perfusates of both ischemic models significantly increased after 30 min of reperfusion. Recombinant rat TNF-α (50,000 U), placed into perfusate after baseline measurements, produced no measurable change in microvascular permeability in control lungs perfused over the same time period (135 min), but I/R injury was significantly enhanced in the presence of TNF-α. An anti-TNF-α antibody (10 mg/rat) injected intraperitoneally into rats 2 h before the lung was isolated prevented the microvascular damage in lungs exposed to both I/R and V˙/R ( P < 0.001). These results indicate that TNF-α is an essential component at the cascade of events that cause lung endothelial injury in short-term I/R andV˙/R models of lung ischemia.

Myocardial tumor necrosis factor-α secretion in hypertensive and heart failure-prone rats

1999 ◽  
Vol 277 (2) ◽  
pp. H543-H550 ◽  
Author(s):  
Marina R. Bergman ◽  
Ruey H. Kao ◽  
Sylvia A. McCune ◽  
Bethany J. Holycross
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Tnf Α ◽  
Necrosis Factor

Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-α production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-α production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-α and inhibition of TNF-α secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-α, but secretion decreased with age. SHR and SHHF rats secreted more TNF-α than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-α at 18 mo. Amrinone inhibited TNF-α secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-α secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-α, and, although hypertension, per se, did not maintain elevated cardiac TNF-α levels, SHHF rats increase TNF-α production during the end stages of failure.

scholarly journals TNF-α: A Benificial or Harmful Pathogenic Cytokine in Cardiovascular System

2021 ◽  
Vol 11 (1) ◽  
pp. 114-120
Author(s):  
Sunny Dhiman ◽  
Inder Kumar ◽  
Priyankul Palia ◽  
Shalini Jamwal ◽  
Pankaj Kumar
Keyword(s):  
Tumor Necrosis Factor ◽  
Cardiovascular System ◽  
Tumor Necrosis ◽  
Pressure Overload ◽  
Future Research ◽  
Preventive Action ◽  
Beneficial Effects ◽  
Tnf Α ◽  
Necrosis Factor

Tumor necrosis factor (TNF- alpha) plays important role in pathophysiology of cardiovascular system and had been comprehensively studied over the last 20 years.  These studies demonstrate both Detrimental and potentially conflicting roles of TNF-α in pathophysiology of heart. Beneficial effects of TNF-α includes cardioprotective action against ischemia, myocarditis, pressure overload and preventive action against potential adverse effects including development of atherosclerosis, reperfusion injury, hypertrophy, and heart failure. However, TNF-α is still controversial for its beneficial or harmful effects for cardiovascular system. This review includes evaluation of possible role of TNF-α in cardiovascular system specifically in pathophysiology and morphology of cardiomyocytes. Further this article mainly emphases on the claimed role of TNF-α pathways with concerning essential cardiac cellular processes which may have unswerving adaptive effects in the heart with respect to future research directions.  Keywords: Tumor Necrosis Factor, Hypertrophy, Pathophysiology, Cytokine, Pathology, Cardiovascular System.

scholarly journals Relationship of Endothelin-1, Tumor Necrosis Factor-alpha and Interleukin-6 with the Progression of Heart Failure

2009 ◽  
Vol 1 (2) ◽  
pp. 45
Author(s):  
Mona Yolanda ◽  
Marsetio Donosepoetro ◽  
Anwar Santoso
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Significant Positive Correlation ◽  
Systolic Heart Failure ◽  
Tnf Α ◽  
Relationship Of ◽  
The Relationship ◽  
Necrosis Factor

BACKGROUNDS: Heart failure, a new epidemic of cardiovascular disease, has become an important issue and its prognosis is poor. Heart failure is the condition where the impaired heart cannot pump enough blood to provide the needs of metabolic tissues and organs. Early diagnosis of heart failure is really crucial to determine the success of treatment and to prevent further myocardial dysfunction and worsening clinical symptoms. This condition can be worsened by ET-1, which triggers the secretion of IL-6 and TNF-α as pro inflammation factors. In Systolic Heart Failure, systolic function changes are accompanied by changes in diastolic function. Thus, the condition of systolic heart failure is worse than Diastolic Heart Failure. The purpose of this study is to assess the relationship of ET-1 with diastolic and systolic heart failure groups and the relationship of ET-1 with TNF-α and IL-6 as pro inflammation factors.METHODS: The design of this study was cross-sectional analysis on 62 patients with heart failure, grouped according to the classification of diastolic and systolic heart failure.RESULTS: A significant positive correlation of ET-1 with diastolic and systolic heart failure was found (p=0.008; r=0.324). A significant positive correlation was also found between ET-1 and IL-6 (p=0.001; r=0.393), but a less significant correlation was noted between ET-1 and TNF-α (p=0.201; r=-0.158).CONCLUSIONS: ET-1 has the strongest correlation (p=0.033) with prevalence ratio 3.930 and can differentiate between Diastolic and Systolic Heart Failure.KEYWORDS: Endothelin-1 (ET-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), heart failure

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