Tnf-alpha Blockade Decreases Oxidative Stress in the Paraventricular Nucleus and Attenuates Sympathoexcitation in Heart Failure Rats.
From: School of Veterinary Medicine, Comparative Biomedical Sciences Department, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
American journal of physiology. Heart and circulatory physiology
- Publish Date: Jul 2007
- ISSN: 0363-6135
- Volume: 293
- Issue: 1
- Pages: H599-609
- Medium: Print
- Language: English
- Citation (JAMA): Guggilam Anuradha, Haque Masudul, Kerut Edmund Kenneth, et al. Tnf-alpha Blockade Decreases Oxidative Stress in the Paraventricular Nucleus and Attenuates Sympathoexcitation in Heart Failure Rats.. Am. J. Physiol. Heart Circ. Physiol. Jul 2007;293:H599-609
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.
Mesh Headings (Keywords): Animals, Blood Pressure, Cardiac Output, Low, Free Radical Scavengers, Heart Rate, Male, Oxidative Stress, Paraventricular Hypothalamic Nucleus, Pentoxifylline, Rats, Rats, Sprague-Dawley, Sympathetic Nervous System, Tumor Necrosis Factor-alpha
Check for Full Text / PubMed Unique Identifier (PMID): 17416605
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