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

Abstract

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)-alpha 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-alpha, 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-alpha 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-alpha 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.

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

“…Tissue NE concentration was measured using HPLC with electrochemical detection (HTEC-500, Eicom Corporation, Japan) as previously described (Barber et al 2003;Yang et al 2008;Kang et al 2009a). Plasma NE was measured using HPLC as previously described (Guggilam et al 2007(Guggilam et al , 2008.…”

“…Total RNA was extracted from PVN tissues and nNOS and AT1-R mRNA expression was determined by real-time RT-PCR and normalized to GAPDH levels as previously described (Guggilam et al 2007(Guggilam et al , 2008Sriramula et al 2008;Kang et al 2009b).…”

“…Maximum RSNA was detected using an intravenous bolus administration of sodium nitroprusside (SNP, 10 μ g) (Nagura et al 2004;Kang et al 2009a). At the end of the experiment, the background noise, defined as the signal-recorded postmortem, was subtracted from actual RSNA and subsequently expressed as percent of maximum (in response to SNP) (Liu et al 2000;Guggilam et al 2007). The left ventricular end-diastolic pressure (LVEDP), the right ventricle (RV)/body weight (BW) ratio and lung/BW ratio were measured as previously described (Kang et al 2008a(Kang et al , 2009a.…”

Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats

“…This in turn affects a variety of downstream signaling pathways, including activation of Ca 2ϩ -sensitive channels (47,54) and changes in the intracellular kinase/phosphatase balance (8), all of which can in turn further alter neuronal excitability following NMDA receptor activation. Moreover, other signaling mechanisms known to contribute to altered neuronal function in HF rats, including nitric oxide (NO) and reactive oxygen species (ROS) production (4,22,26,68), are strongly dependent on or influenced by NMDA-mediated increases in intracellular Ca 2ϩ . The functional consequences of ⌬Ca 2ϩ are largely dependent on its magnitude and time course.…”

The inextricable role of the kidney in hypertension

“…NF-κB activation within the vascular endothelium drives hypertensive renal damage without measurable effects on blood pressure suggesting a direct role in end-organ damage (68). Within cardiovascular control centers in the brain, NF-κB activation potently enhances sympathetic outflow (69)(70)(71), which could potentially promote sodium retention in the kidney via stimulation of renal sympathetic nerves. Within kidney parenchymal cells, induction of oxidative stress leads to NF-κB nuclear translocation, impaired sodium excretion, and blood pressure elevation by disrupting D1 dopamine receptor function (72).…”