Increased cyclooxygenase-2 expression in hypothalamic paraventricular nucleus in rats with heart failure: role of nuclear factor kappaB.

We investigated the role of nuclear factor kappaB (NF-kappaB) 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-kappaB 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-1beta and norepinephrine in plasma and prostaglandin E2 in cerebrospinal fluid. In the PVN, NF-kappaB p50 precursor p105 mRNA increased, and mRNA for its inhibitor, IkappaB, 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 IkappaB 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-1beta. Pyrrolidine dithiocarbamate and eplerenone had no effect on plasma aldosterone. The results suggest that activation of NF-kappaB 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.