Published online before print January 22, 2007, doi: 10.1161/01.HYP.0000257356.20527.c5
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(Hypertension. 2007;49:511.)
© 2007 American Heart Association, Inc.
Original Articles |
Increased Cyclooxygenase-2 Expression in Hypothalamic Paraventricular Nucleus in Rats With Heart Failure
Role of Nuclear Factor 
B
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.
Correspondence to Robert B. Felder, University of Iowa College of Medicine, E318-GH, 200 Hawkins Dr, Iowa City, IA 52242. E-mail robert-felder{at}uiowa.edu
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-1ß 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-1ß. 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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