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.

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 Tumor Necrosis Factor α Regulates Responses to Nerve Growth Factor, Promoting Neural Cell Survival but Suppressing Differentiation of Neuroblastoma Cells

2008 ◽  
Vol 19 (3) ◽  
pp. 855-864 ◽  
Author(s):  
Yoshinori Takei ◽  
Ronald Laskey
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Neuroblastoma Cells ◽  
Erk Activation ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Although nerve growth factor (NGF) promotes survival of neurons, tumor necrosis factor α (TNF-α) contributes to cell death triggered by NGF depletion, through TNF-α receptor (TNFR) 1. In contrast to this effect, TNF-α can promote neural cell survival via TNF-α receptor TNFR2. Although these findings demonstrate pivotal roles of TNF-α and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-α synthesis through the nuclear factor-κB transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-α. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, extracellular signal-regulated kinase (Erk) and Akt. It increases Erk activation by NGF, and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-α signaling decreases NGF-dependent survival of neurons from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-α cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-α suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.

Abstract P317: Sex Differences in the Hemodynamic and Sympathetic Responses to Centrally Administered Tumor Necrosis Factor-α in Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Shun-Guang Wei ◽  
Yang Yu ◽  
Robert B Felder
Keyword(s):  
Heart Failure ◽  
Sex Differences ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Female Rats ◽  
Male Rats ◽  
Tnf Α ◽  
Estrogen Effect ◽  
Factor Α ◽  
Necrosis Factor

Introduction: Accumulating evidence indicates that sex differences exist in the clinical and experimental outcomes of various cardiovascular diseases. In addition to its protective effect on renin-angiotensin system activity, estrogen has an anti-inflammatory influence. The central actions of pro-inflammatory cytokines (PICs) contribute significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. In male adult rat, central administration of PICs induces substantial increases in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA), and blocking PICs reduces sympathetic excitation in experimental models of hypertension and heart failure. Whether PICs have similar central sympatho-excitatory effects in the female rat remains unknown. Hypothesis: We hypothesized that female rats may be protected from the central cardiovascular and autonomic effects of PICs. Methods: Urethane anesthetized male and female Sprague Dawley rats (10-12 weeks) underwent an intracerebrovascular (ICV) injection of the prototypical PIC tumor necrosis factor-α (TNF-α, 100 ng). BP (mmHg), HR (beats/min) and RSNA (% change) responses were continuously recorded for 4-5 hours. Results: In male rats (n=6), ICV TNF-α induced a dramatic and long-lasting increase (*p<0.001 vs. baseline) in BP (23.1 ± 2.5*), HR (82 ± 8*) and RSNA (109.5 ± 4.3 %*), that began within 20-30 mins and peaked at 90-120 mins after ICV injection. In the female rats (n=6), ICV TNF-α elicited significantly (p<0.05) smaller increases (*p<0.001 vs. baseline) in BP (14.8 ± 1.8*), HR (55 ± 6*) and RSNA (78.5 ± 6.3*), compared with the male rats. Conclusion: These data demonstrate a sex difference in the cardiovascular and sympathetic responses to centrally administered PICs. Whether the observed differences can be explained by an estrogen effect on TNF-α signaling per se or by an estrogen effect on TNF-α-induced renin-angiotensin activity remains to be determined. However, a reduced response of female rats to central inflammation may be an important contributor to sex differences in pathophysiology of hypertension and heart failure.

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.

scholarly journals Inhibition by Interleukin-1β and Tumor Necrosis Factor-α of the Insulin-Like Growth Factor I Messenger Ribonucleic Acid Response to Growth Hormone in Rat Hepatocyte Primary Culture*

Endocrinology ◽  
1997 ◽  
Vol 138 (3) ◽  
pp. 1078-1084 ◽  
Author(s):  
Jean-Paul Thissen ◽  
Josiane Verniers
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mrna Levels ◽  
Factor I ◽  
Tnf Α ◽  
Igf I ◽  
Necrosis Factor ◽  
I Gene

Abstract The cytokines are the putative mediators of the catabolic reaction that accompanies infection and trauma. Evidence suggests that their catabolic actions are indirect and potentially mediated through changes in hormonal axis such as the hypothalamo-pituitary-adrenal axis. Insulin-like growth factor I (IGF-I) is a GH-dependent growth factor that regulates the protein metabolism. To determine whether cytokines can directly inhibit the production of IGF-I by the liver, we investigated the regulation of IGF-I gene expression by interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α (10 ng/ml) in a model of rat primary cultured hepatocytes. Hepatocytes were isolated by liver collagenase perfusion and cultured on Matrigel 48 h before experiments. Each experiment was performed in at least three different animals. In the absence of GH, IL-1β and TNF-α did not affect the IGF-I messenger RNA (mRNA) basal levels, whereas IL-6 increased it by a factor of 2.5 after 24 h (P &lt; 0.05). GH (500 ng/ml) alone stimulated the IGF-I gene expression markedly (5- to 10-fold increase) after 24 h (P &lt; 0.001). IL-1β, and TNF-α to a lesser extent, dramatically inhibited the IGF-I mRNA response to GH (IL-1β: −82%, P &lt; 0.001 and TNF-α: −47%, P &lt; 0.01). The half-maximal inhibition of the IGF-I mRNA response to GH was observed for a concentration of IL-1β between 0.1 and 1 ng/ml. Moreover, IL-1β abolished the IL-6-induced IGF-I mRNA response. In contrast, IL-6 did not impair the IGF-I mRNA response to GH. To determine the potential role of the GH receptor (GHR) and the GH-binding protein (GHBP) in this GH resistance, we assessed the GHR and GHBP mRNAs response to these cytokines. GH alone did not affect the GHR/GHBP mRNA levels. IL-1β markedly decreased the GHR and GHBP mRNA levels (respectively, −68% and −60%, P &lt; 0.05). Neither TNF-α nor IL-6 affected the GHR/GHBP gene expression. In conclusion, our results show that IL-1β, and TNF-α to a lesser extent, blunt the IGF-I mRNA response to GH. The resistance to GH induced by IL-1β might be mediated by a decrease of GH receptors, as suggested by the marked reduction of GHR mRNA. These findings suggest that decreased circulating IGF-I, in response to infection and trauma, may be caused by a direct effect of cytokines at the hepatocyte level.

scholarly journals Inhibition of Mycobacterium bovisBCG-Induced Tumor Necrosis Factor Alpha Secretion in Human Cells by Transforming Growth Factor β

1998 ◽  
Vol 5 (4) ◽  
pp. 588-591 ◽  
Author(s):  
Patricia Méndez-Samperio ◽  
Marisol Hernandez-Garay ◽  
Angela Nuñez Vazquez
Keyword(s):  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Human Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT The effect of exogenous transforming growth factor β (TGF-β) onMycobacterium bovis BCG-induced tumor necrosis factor alpha (TNF-α) production by human mononuclear cells was studied. It was found that TNF-α production by human cells stimulated with BCG was significantly inhibited by TGF-β. The specificity of the observed inhibition was demonstrated, since the addition of an anti-TGF-β neutralizing monoclonal antibody completely reversed the inhibitory effect. Furthermore, the suppressive effect of TGF-β on TNF-α secretion in this system was not due to a direct cytotoxic effect, since cell viability was comparable in the presence or absence of TGF-β. Interestingly, our results demonstrated comparative suppressive effects of TGF-β and interleukin-10 on BCG-induced TNF-α secretion. Together, the data demonstrate, for the first time, that TGF-β inhibits BCG-induced TNF-α secretion by human cells.

Comparisons of the Effects of Anesthesia and Stress on Release of Tumor Necrosis Factor-α, Leptin, and Nitric Oxide in Adult Male Rats

2001 ◽  
Vol 226 (4) ◽  
pp. 296-300 ◽  
Author(s):  
Claudio A. Mastronardi ◽  
Wen H. Yu ◽  
Samuel M. McCann
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Adult Male ◽  
Tumor Necrosis ◽  
Fold Increase ◽  
Male Rats ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Bacterial lipopolysaccharide (LPS) stimulates massive release of tumor necrosis factor-alpha (TNF-α) together with nitric oxide (NO) and a lessor release of leptin. We hypothesized that other types of stress such as that of surgery might also release these cytokines and NO. Adult male rats were anesthetized with ketamine/acepromazine/xylazine anesthesia (90 + 2 + 6 mg/ml, respectively) and an external jugular catheter was inserted for removal of blood samples (0.6 ml) at various times postoperatively. Plasma TNF-α was almost undetectable in decapitated rats and was near zero immediately following the placement of the jugular catheter (time zero [to]). As the rats awakened from anesthesia, there was a rise in TNF-α at 30 min that peaked at 2 hr with a 400-fold increase and then precipitously declined 40-fold to a level still greater than zero at 3 hr. At 6 hr on the following morning, TNF-α values were near zero, but following connection of tubing and withdrawal of the initial blood sample, there was a 100-fold increase 1 hr later, followed by a decline over the next 3 hr. In contrast, plasma [NO3/NO2] from decapitated rats was 117 μM. Values at t0 were decreased and plummeted 4-fold within 30 min, then rose slightly in the ensuing 3 hr. At 6 hr on the next day [NO3/NO2] values were lower than at t0 and declined gradually during the next 4 hr. Leptin gradually declined from pre-operative concentrations, reaching a minimum at 3 hr and its concentration was unaffected by the bleeding stress of the second day. We conclude that release of TNF-α, [NO3/NO2], and leptin are neurally controlled since plasma levels of all three declined as a result of anesthesia. TNF-α secretion was remarkably stress responsive, whereas NO release appeared to be suppressed by the combined operative and bleeding stress, and leptin was stress unresponsive.

Epidermal growth factor, tumor necrosis factor alpha, and thioredoxin in cerebral tissue following cerebral ischemia / Serebral iskemi sonrası beyin dokusunda epidermal büyüme faktörü, tümör nekrozis faktör alfa ve tiyoredoksin

2015 ◽  
Vol 40 (6) ◽  
Author(s):  
Hatice Ferhan Kömürcü ◽  
Nedret Kılıç ◽  
Melike Erol Demirbilek ◽  
Serdar Kahraman
Keyword(s):  
Cerebral Ischemia ◽  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cerebral Tissue ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Epidermal Growth ◽  
Factor Alpha ◽  
Necrosis Factor

AbstractObjective: In this study, the changes in the levels of the epidermal growth factor (EGF), tumor necrosis factor alpha (TNF-α), and thioredoxine (TRX) in the cerebral tissue of rats following the cerebral ischemia model were investigated.Methods: The left middle cerebral artery occlusion (MCAO) was done in 27 out of 48 rats recruited into the study for obtaining focal cerebral ischemia model (MCAO group). Twenty-one rats underwent a sham operation; the middle cerebral artery was exposed but not occluded (Sham group). EGF, TNF-α, and TRX levels were studied in the operated left and contralateral hemispheres at the 16Results: EGF levels at 96Conclusion: The results suggested that cerebral ischemia following MCAO might affect EGF, TNF-α and TRX levels in both ischemic and contralateral hemispheres in cerebral tissue; and this effect may change by the time passed after MCAO.

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