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.
Yu
Yang
Y
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Kang
Yu-Ming
YM
Zhang
Zhi-Hua
ZH
Wei
Shun-Guang
SG
Chu
Yi
Y
Weiss
Robert M
RM
Felder
Robert B
RB
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016207:Cytokines; D004195:Disease Models, Animal; D000077545:Eplerenone; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D013148:Spironolactone; D000077545:Eplerenone; D051546:Cyclooxygenase 2