Published Online
on January 22, 2007

A more recent version of this article appeared on March 1, 2007

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Submitted on October 10, 2006
Revised on October 31, 2006

Increased Cyclooxygenase-2 Expression in Hypothalamic Paraventricular Nucleus in Rats With Heart Failure. Role of Nuclear Factor B

Yang Yu; Yu-Ming Kang; Zhi-Hua Zhang; Shun-Guang Wei; Yi Chu; Robert M. Weiss; and Robert B. Felder^*

From the Department of Internal Medicine (Y.Y., Y.-M.K., Z.-H.Z., S.-G.W., Y.C., R.M.W., R.B.F.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and the Veterans Affairs Medical Center (R.M.W., R.B.F.), Iowa City, Iowa.

^* To whom correspondence should be addressed. E-mail: robert-felder{at}uiowa.edu.

Abstract--We investigated the role of nuclear factor B (NF-B) in the cytokine-mediated induction of cyclooxygenase-2 activity in the paraventricular nucleus of hypothalamus (PVN), a critical cardiovascular and autonomic center, in rats with heart failure (HF). Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. HF rats were treated orally for 6 weeks with vehicle (tap water), the NF-B inhibitor pyrrolidine dithiocarbamate (150 mg/kg per day), or the mineralocorticoid receptor antagonist eplerenone (30 mg/kg per day), which has been shown to reduce circulating proinflammatory cytokines in this model. Compared with sham surgery, HF rats had higher (P<0.05) levels of aldosterone, interleukin-1 and norepinephrine in plasma and prostaglandin E₂ in cerebrospinal fluid. In the PVN, NF-B p50 precursor p105 mRNA increased, and mRNA for its inhibitor, IB, decreased (P<0.05). Cyclooxygenase-2 mRNA and protein expression was increased in perivascular cells of the PVN. Both pyrrolidine dithiocarbamate and eplerenone reduced (P<0.05) p105 mRNA and increased IB mRNA in PVN. Both also reduced (P<0.05) cyclooxygenase-2 mRNA and protein expression in PVN, cerebrospinal fluid prostaglandin E₂, and plasma norepinephrine. Eplerenone, but not pyrrolidine dithiocarbamate, reduced plasma interleukin-1. Pyrrolidine dithiocarbamate and eplerenone had no effect on plasma aldosterone. The results suggest that activation of NF-B is an intermediary step in cytokine-mediated induction of cyclooxygenase-2 in the PVN of HF rats. By enhancing access of prostaglandin E₂ to hypothalamic neurons, this mechanism may contribute to augmented sympathetic nerve activity in HF.

Key words: cytokines • mineralocorticoid receptor • cyclooxygenase-2 • nuclear factor-kappa B • heart failure

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