TNF-alpha blockade decreases oxidative stress in the paraventricular nucleus and attenuates sympathoexcitation in heart failure rats.
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.
Guggilam
Anuradha
A
School of Veterinary Medicine, Comparative Biomedical Sciences Department, Louisiana State University, 1909 Skip Bertman Drive, Baton Rouge, LA 70803, USA.
Haque
Masudul
M
Kerut
Edmund Kenneth
EK
McIlwain
Elizabeth
E
Lucchesi
Pamela
P
Seghal
Inder
I
Francis
Joseph
J
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000503:physiopathology*; D016166:Free Radical Scavengers / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D010431:Pentoxifylline / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D016166:Free Radical Scavengers; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline