TNF-α blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats

2007 ◽  
Vol 293 (1) ◽  
pp. H599-H609 ◽  
Author(s):  
Anuradha Guggilam ◽  
Masudul Haque ◽  
Edmund Kenneth Kerut ◽  
Elizabeth McIlwain ◽  
Pamela Lucchesi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Coronary Artery Ligation ◽  
Tei Index ◽  
Artery Ligation ◽  
Tnf Α ◽  
Mrna And Protein Expression ◽  
Necrosis Factor ◽  
Renal Sympathetic

Oxidative stress plays an important role in the pathophysiology of cardiovascular disease. Recent evidence suggests that cytokines induce oxidative stress and contribute to cardiac dysfunction. In this study, we investigated whether increased circulating and tissue levels of tumor necrosis factor (TNF)-α in congestive heart failure (CHF) modulate the expression of NAD(P)H oxidase subunits, Nox2 and its isoforms, in the paraventricular nucleus (PVN) of the hypothalamus and contribute to exaggerated sympathetic drive in CHF. Heart failure was induced in Sprague-Dawly rats by coronary artery ligation and was confirmed using echocardiography. Pentoxifylline (PTX) was used to block the production of cytokines for a period of 5 wk. CHF induced a significant increase in the production of reactive oxygen species (ROS) in the left ventricle (LV) and in the PVN. The mRNA and protein expression of TNF-α, Nox1, Nox2, and Nox4 was significantly increased in the LV and PVN of CHF rats. CHF also decreased ejection fraction, increased Tei index, and increased circulating catecholamines (epinephrine and norepinephrine) and renal sympathetic activity (RSNA). In contrast, treatment with PTX in CHF rats completely blocked oxidative stress and decreased the production of TNF-α and Nox2 isoforms both in the LV and PVN. PTX treatment also decreased catecholamines and RSNA and prevented further decrease in cardiac function. In summary, TNF-α blockade attenuates ROS and sympathoexcitation in CHF. This study unveils new mechanisms by which cytokines play a role in the pathogenesis of CHF, thus underscoring the importance of targeting cytokines in heart failure.

Central mineralocorticoid receptor blockade decreases plasma TNF-α after coronary artery ligation in rats

2003 ◽  
Vol 284 (2) ◽  
pp. R328-R335 ◽  
Author(s):  
Joseph Francis ◽  
Robert M. Weiss ◽  
Alan Kim Johnson ◽  
Robert B. Felder
Keyword(s):  
Heart Failure ◽  
Central Nervous System ◽  
Nervous System ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Evaluation Study ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Tnf Α ◽  
The Central Nervous System

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3rd cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-α (TNF-α) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-α levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-α release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-α production.

New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

2004 ◽  
Vol 287 (1) ◽  
pp. H340-H350 ◽  
Author(s):  
C. Berthonneche ◽  
T. Sulpice ◽  
F. Boucher ◽  
L. Gouraud ◽  
J. de Leiris ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Pressure ◽  
Subsequent Development ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Direct Role ◽  
Volume Curve ◽  
Tnf Α

A marked increase in plasma TNF-α has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-α receptor type II (sTNF-RII, 40 μg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-α, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI ( P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-α plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

scholarly journals Heart failure-induced changes of voltage-gated Ca2+ channels and cell excitability in rat cardiac postganglionic neurons

2014 ◽  
Vol 306 (2) ◽  
pp. C132-C142 ◽  
Author(s):  
Huiyin Tu ◽  
Jinxu Liu ◽  
Dongze Zhang ◽  
Hong Zheng ◽  
Kaushik P. Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Coronary Artery Ligation ◽  
Patch Clamp Recording ◽  
Artery Ligation ◽  
Cell Excitability ◽  
Autonomic Imbalance ◽  
Mrna And Protein Expression ◽  
Induced Changes ◽  
Channel Currents

Chronic heart failure (CHF) is characterized by decreased cardiac parasympathetic and increased cardiac sympathetic nerve activity. This autonomic imbalance increases the risk of arrhythmias and sudden death in patients with CHF. We hypothesized that the molecular and cellular alterations of cardiac postganglionic parasympathetic (CPP) neurons located in the intracardiac ganglia and sympathetic (CPS) neurons located in the stellate ganglia (SG) possibly link to the cardiac autonomic imbalance in CHF. Rat CHF was induced by left coronary artery ligation. Single-cell real-time PCR and immunofluorescent data showed that L (Cav1.2 and Cav1.3), P/Q (Cav2.1), N (Cav2.2), and R (Cav2.3) types of Ca2+ channels were expressed in CPP and CPS neurons, but CHF decreased the mRNA and protein expression of only the N-type Ca2+ channels in CPP neurons, and it did not affect mRNA and protein expression of all Ca2+ channel subtypes in the CPS neurons. Patch-clamp recording confirmed that CHF reduced N-type Ca2+ currents and cell excitability in the CPP neurons and enhanced N-type Ca2+ currents and cell excitability in the CPS neurons. N-type Ca2+ channel blocker (1 μM ω-conotoxin GVIA) lowered Ca2+ currents and cell excitability in the CPP and CPS neurons from sham-operated and CHF rats. These results suggest that CHF reduces the N-type Ca2+ channel currents and cell excitability in the CPP neurons and enhances the N-type Ca2+ currents and cell excitability in the CPS neurons, which may contribute to the cardiac autonomic imbalance in CHF.

scholarly journals ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction

2016 ◽  
Vol 310 (6) ◽  
pp. H732-H739 ◽  
Author(s):  
Yang Yu ◽  
Shun-Guang Wei ◽  
Zhi-Hua Zhang ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Mapk Signaling ◽  
Coronary Artery Ligation ◽  
Nerve Activity ◽  
Artery Ligation

Brain MAPK signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether decreasing ERK1/2 (also known as p44/42 MAPK) signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympathoexcitatory mediators in the PVN and augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or sham operation, small interfering (si)RNAs targeting ERK1/2 or a nontargeting control siRNA was microinjected bilaterally into the PVN. Experiments were conducted 5–7 days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot analysis confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fos-related antigen-like-immunoreactive neurons), lower plasma norepinephrine levels, and improved peripheral manifestations of HF compared with HF rats treated with control siRNAs. These results demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction and may be a novel target for therapeutic intervention.

scholarly journals Dl-3-n-Butylphthalide Promotes Cardiac Function, Inhibit Oxidative Stress and Myocardial Apoptosis of Chronic Heart Failure Mice via Stimulating Nrf2/HO-1 pathway

2021 ◽  
Author(s):  
Zhongyu Wang ◽  
Yan Zhang ◽  
Chun Yang ◽  
Hongliang Yang
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Signaling Pathway ◽  
Myocardial Injury ◽  
Heart Function ◽  
Regulatory Protein ◽  
Camp Response Element Binding ◽  
Tunel Staining ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Abstract PurposeHeart failure (HF) continues to threat the human health and plagues the world, however, there are limited effective drugs for HF. We aimed to investigate the protective effect of Dl-3-n-Butylphthalide (NBP) on myocardial injury in heart failure mice, and to study regulation mechanisms with Nrf2/HO-1/Ca2+-SERCA2a axis. MethodsSixty C57BL/6J mice were grouped into five groups using a random number table: sham group (Sham), Heart Failure model group (HF), Heart Failure+ NBP group (HN), Heart Failure+NBP+Nrf2 inhibitor (HNM), Heart Failure+ NBP + calmodulin-dependent protein kinase II (CaMKⅡ) antagonist, KN93 (HNK). The HF mice was prepared using left anterior descending coronary artery ligation. As animal model preparation, the heart function was detected using echocardiography. H&E and MASSON trichrome staining were performed to identify myocardial injury; The apoptosis of myocardial was examined by TUNEL staining assay. The levels of different oxidative stress-related proteins were measured through ELISA assay ; The reactive oxygen species and Nrf2 expression in heart tissue were observed with immunofluorescence assay. The levels of SERCA2a, calmodulin, endoplasmic reticulum stress regulatory protein and Nrf2/HO-1 protein were measured using western blotting. ResultsThe results demonstrated that NBP can significantly promote heart function, relieve the injury and inhibit cell apoptosis, meanwhile, reduce ERS injury in heart failure mice through increasing SERCA2a level and reducing Ca2+ influx. Finally, NBP was demonstrated to reduce CaMKⅡphosphorylation levels and decrease cAMP-response element binding protein phosphorylation levels, which suggested that NBP could also activate Nrf2/HO-1 signaling pathway. ConclusionsThis study identified that NPBs treatment promotes the cardiomyocytes ERS and alleviates myocardial injury in heart failure mice which is related with stimulating Nrf2/HO-1 signaling pathway, regulating Ca2+-SERCA2a and reducing Ca2+ influx.

Altered nitric oxide mechanism within the paraventricular nucleus contributes to the augmented carotid body chemoreflex in heart failure

2007 ◽  
Vol 292 (1) ◽  
pp. H149-H157 ◽  
Author(s):  
Maram K. Reddy ◽  
Harold D. Schultz ◽  
Hong Zheng ◽  
Kaushik P. Patel
Keyword(s):  
Nitric Oxide ◽  
Heart Failure ◽  
Paraventricular Nucleus ◽  
Carotid Body ◽  
Coronary Artery Ligation ◽  
Nerve Activity ◽  
Artery Ligation ◽  
Peripheral Chemoreceptor ◽  
Arterial Blood ◽  
Peripheral Chemoreflex

Our previous study demonstrated a contribution of the paraventricular nucleus (PVN) of the hypothalamus in the processing of the carotid body (CB) chemoreflex. Nitric oxide (NO) (within the PVN), known to modulate autonomic function, is altered in rats with heart failure (HF). Therefore, the goal of the present study was to examine the influence of endogenous and exogenous NO within the PVN on the sympathoexcitatory component of the peripheral chemoreflex in normal and HF states. We measured mean arterial blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) in sham-operated and HF rats (6–8 wk after coronary artery ligation) after incremental doses of potassium cyanide (25–100 μg/kg iv). There was potentiation of the reflex responses in HF compared with sham-operated rats. Bilateral microinjection of an inhibitor of NO synthase, NG-monomethyl-l-arginine (50 pmol), into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation in sham-operated rats but had no effect in HF rats. Conversely, bilateral microinjection of a NO donor, sodium nitroprusside (50 nmol), into the PVN attenuated the RSNA response of the peripheral chemoreflex in sham-operated rats but to a smaller extent in HF rats. These data indicate that 1) NO within the PVN plays an important role in the processing of the CB chemoreflex and 2) there is an impairment of the NO function within the PVN of HF rats, which contributes to an augmented peripheral chemoreflex and subsequent elevation of sympathetic activity in HF.

scholarly journals Altered Na/Ca exchange distribution in ventricular myocytes from failing hearts

2016 ◽  
Vol 310 (2) ◽  
pp. H262-H268 ◽  
Author(s):  
Hanne C. Gadeberg ◽  
Simon M. Bryant ◽  
Andrew F. James ◽  
Clive H. Orchard
Keyword(s):  
Heart Failure ◽  
Ventricular Myocytes ◽  
Cell Voltage ◽  
Coronary Artery Ligation ◽  
Sham Operation ◽  
Ca Current ◽  
Artery Ligation ◽  
Whole Cell ◽  
Rat Hearts ◽  
T Tubules

In mammalian cardiac ventricular myocytes, Ca efflux via Na/Ca exchange (NCX) occurs predominantly at T tubules. Heart failure is associated with disrupted t-tubular structure, but its effect on t-tubular function is less clear. We therefore investigated t-tubular NCX activity in ventricular myocytes isolated from rat hearts ∼18 wk after coronary artery ligation (CAL) or corresponding sham operation (Sham). NCX current ( INCX) and l-type Ca current ( ICa) were recorded using the whole cell, voltage-clamp technique in intact and detubulated (DT) myocytes; intracellular free Ca concentration ([Ca]i) was monitored simultaneously using fluo-4. INCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell INCX was not significantly different in Sham and CAL myocytes and occurred predominantly in the T tubules in Sham myocytes. CAL was associated with redistribution of INCX and ICa away from the T tubules to the cell surface and an increase in t-tubular INCX/ ICa density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular INCX in CAL myocytes was accompanied by an increase in the fraction of Ca sequestered by SR. However, SR Ca content was not significantly different in Sham, Sham DT, and CAL myocytes but was significantly increased by DT of CAL myocytes. In Sham myocytes, there was hysteresis between INCX and [Ca]i, which was absent in DT Sham but present in CAL and DT CAL myocytes. These data suggest altered distribution of NCX in CAL myocytes.

Abstract P237: Is Ischemia/Reperfusion an Efficient Method for Producing Heart Failure in Rats?

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana Carolina M Omoto ◽  
Fábio N Gava ◽  
Mauro de Oliveira ◽  
Carlos A Silva ◽  
Rubens Fazan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Mitral Annulus ◽  
Mortality Rates ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.

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.

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