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Am J Physiol Heart Circ Physiol (April 6, 2007). doi:10.1152/ajpheart.00286.2007
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Submitted on March 7, 2007
Accepted on March 30, 2007

TNF-{alpha} BLOCKADE DECREASES OXIDATIVE STRESS IN THE PARAVENTRICULAR NUCLEUS AND ATTENUATES SYMPATHOEXCITATION IN HEART FAILURE RATS

Anuradha Guggilam1, Masudul Haque1, Edmund Kenneth Kerut2, Elizabeth McIIwain2, Pamela A. Lucchesi2, Inder Sehgal1, and Joseph Francis1*

1 Comparative Biomedical Sciences, Louisiana State University, Baton Rouge, Louisiana, United States
2 Department of Physiology and Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana, United States

* To whom correspondence should be addressed. E-mail: jfrancis{at}lsu.edu.

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 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 weeks. 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 were significantly increased in the LV and PVN of CHF rats. CHF also decreased ejection fraction, increased Tei index, 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.




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