NF-κB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure

• DOI: 10.1007/s00395-011-0215-7
• Publication Date: 2011-09-06T13:43:11Z
• Authors: Yu-Ming Kang; Feng Gao; Hui-Hua Li; Jeffrey P. Cardinale; Carrie Elks; Wei-Jin Zang; Xiao-Jing Yu; Yan-Yan Xu; Jie Qi; Qing Yang; Joseph Francis
• Keywords: Heart Failure; Male; 0301 basic medicine; Neurotransmitter Agents; Sympathetic Nervous System; Blotting, Western; NF-kappa B; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Echocardiography; Animals; Peptides; Paraventricular Hypothalamic Nucleus

Findings from our laboratory indicate that proinflammatory cytokines and their transcription factor, nuclear factor-kappaB (NF-κB), are increased in the hypothalamic paraventricular nucleus (PVN) and contribute towards the progression of heart failure. In this study, we determined whether NF-κB activation within the PVN contributes to sympathoexcitation via interaction with neurotransmitters in the PVN during the pathogenesis of heart failure. Heart failure was induced in rats by left anterior descending coronary artery ligation. Sham-operated control (SHAM) or heart failure rats were treated for 4 weeks through bilateral PVN infusion with SN50, SN50M or vehicle via osmotic minipump. Rats with heart failure treated with PVN vehicle or SN50M (inactive peptide for SN50) had increased levels of glutamate, norepinephrine (NE), tyrosine hydroxylase (TH), superoxide, gp91(phox) (a subunit of NAD(P)H oxidase), phosphorylated IKKβ and NF-κB p65 activity, and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN compared with those of SHAM rats. Plasma levels of cytokines, norepinephrine, epinephrine and angiotensin II, and renal sympathetic nerve activity (RSNA) were increased in heart failure rats. Bilateral PVN infusion of SN50 prevented the decreases in PVN GABA and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH, superoxide, gp91(phox), phosphorylated IKKβ and NF-κB p65 activity observed in vehicle or SN50M-treated heart failure rats. A same dose of SN50 given intraperitoneally did not affect neurotransmitters concentration in the PVN and was similar to vehicle-treated heart failure rats. These findings suggest that NF-κB activation in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced heart failure.