Cross-talk between cytokines and renin-angiotensin in hypothalamic paraventricular nucleus in heart failure: Role of nuclear factor-κB

Abstract

Aims: Nuclear factor-kappa B (NF-κB) is a potent inducer of pro-inflammatory cytokines (PIC) and oxidative stress in cardiovascular disease. In this study, we determined whether upregulation of NF-κB in the hypothalamic paraventricular nucleus (PVN) contributed to neurohumoral excitation either directly, or via interaction with the renin-angiotensin system (RAS), in heart failure (HF). Methods and results: Rats were implanted with intracerebroventricular (ICV) cannulae and subjected to coronary artery ligation, or sham surgery (SHAM). Subsequently, animals were ICV treated with the angiotensin type 1 receptor (AT1-R) antagonist losartan (LOS, 20 μg/h), or SN50 (2 μg/h), which inhibits nuclear translocation of NF-κB, or tempol (TEMP, 80 μg/h), a membrane-permeable superoxide scavenger, or vehicle for 4 weeks. HF induced a significant increase in the expression of AT1-R, PIC, and NAD(P)H oxidase genes and NF-κB p50 in the PVN and in plasma norepinephrine (NE) levels when compared with SHAM rats. In contrast, ICV LOS, SN50, or TEMP attenuated PIC, NF-κB p50, AT1-R and NAD(P)H oxidase genes in the PVN compared with vehicle-treated HF rats. Treatment with LOS, SN50, or TEMP also reduced plasma levels of NE, angiotensin II, and PIC, and decreased left ventricular end diastolic pressure. Conclusion: These findings indicate that NF-κB mediates the cross-talk between RAS and PIC in the PVN in HF, and that superoxide stimulates more NF-κB in the PVN and contributes to neurohumoral excitation. © The Author 2008.